Mesophasic forms of (3s)-aminomethyl-5-methyl-hexanoic acid prodrugs and methods of use

ABSTRACT

Mesophasic forms of (3S)-aminomethyl-5-hexanoic acid prodrugs and methods of preparing and methods of using mesophasic forms of (3S)-aminomethyl-5-hexanoic acid prodrugs are provided.

This application claims the benefit under 35 U.S.C. § 119(e) of U.S.Provisional Application Ser. Nos. 61/023,808 filed Jan. 25, 2008;61/023,813 filed Jan. 25, 2008; and 61/121,859 filed Dec. 11, 2008, eachof which is incorporated by reference in its entirety.

FIELD

Mesophasic forms of (3S)-aminomethyl-5-hexanoic acid prodrugs,pharmaceutical compositions comprising mesophasic forms of(3S)-aminomethyl-5-hexanoic acid prodrugs, and methods of makingmesophasic forms of (3S)-aminomethyl-5-hexanoic acid prodrugs aredisclosed. The crystalline mesophasic forms of(3S)-aminomethyl-5-hexanoic acid prodrugs may be used as therapeuticagents in the treatment of certain diseases and disorders, including,for example, neuropathic pain, epilepsy, generalized anxiety disorder,fibromyalgia, migraine, hot flashes, restless legs syndrome, and sleepdisorders.

BACKGROUND

In general, crystalline forms of drugs are preferred over amorphousforms of drugs, in part, because of their superior stability. Forexample, in many situations, an amorphous drug converts to a crystallinedrug form upon storage. Because amorphous and crystalline forms of adrug typically have different physical/chemical properties, potenciesand/or bioavailabilities, such interconversion is undesirable for safetyreasons in pharmaceutical administration. A key characteristic of anycrystalline drug substance is the polymorphism of such a material.Polymorphs are crystals of the same molecule which have differentphysical properties because the crystal lattice contains a differentarrangement of molecules. The different physical properties exhibited bypolymorphs can affect important pharmaceutical parameters such asstorage, stability, compressibility, density (important in formulationand product manufacturing) and dissolution rates (important indetermining bioavailability). Stability differences may result fromchanges in chemical reactivity (e.g., differential hydrolysis oroxidation, such that a dosage form discolors more rapidly when thedosage form contains one polymorph than another polymorph), mechanicalchanges (e.g., tablets crumble on storage as a kinetically favoredcrystalline form converts to a thermodynamically more stable crystallineform) or both (e.g., tablets of one polymorph are more susceptible tobreakdown at high humidity). Solubility differences between polymorphsmay, in extreme situations, result in transitions to crystalline formsthat lack potency and/or are toxic. In addition, the physical propertiesof the crystalline form may be important in pharmaceutical processing.For example, a particular crystalline form may form solvates morereadily or may be more difficult to filter and wash free of impuritiesthan other forms (e.g., particle shape and size distribution might bedifferent between one crystalline form relative to other forms).

Agencies such as the United States Food and Drug Administration closelyregulate the polymorphic content of the active component of a drug insolid dosage forms. In general, the regulatory agency requiresbatch-by-batch monitoring for polymorphic drugs if anything other thanthe pure, thermodynamically preferred polymorph is marketed.Accordingly, medical and commercial reasons favor synthesizing andmarketing solid drugs as the thermodynamically stable polymorph,substantially free of kinetically favored polymorphs.

(3S)-{[1-Isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoicacid (1),(3S)-{[1-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoicacid (2), and(3S)-{[1-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoic acid(3) are prodrugs of the GABA analog pregabalin,(3S)-aminomethyl-5-methyl-hexanoic acid (4), which have highbioavailability as pregabalin when dosed either orally or directly intothe colon of a mammal (Gallop et al., U.S. Pat. No. 6,972,341; andGallop et al., U.S. Pat. No. 7,186,855, each of which is incorporated byreference in its entirety).

This high oral and/or colonic bioavailability makes these prodrugssuitable for use in oral dosage forms (including sustained-releasedosage forms) useful for treating diseases such as a movement disorder,a gastrointestinal disorder, a psychotic disorder, a mood disorder, ananxiety disorder, a sleep disorder, a pulmonary disorder, aneurodegenerative disorder, an inflammatory disease, neuropathic pain,musculoskeletal pain, chronic pain, migraine, hot flashes, faintnessattacks, urinary incontinence, ethanol withdrawal syndrome, andpremature ejaculation.

Compounds (1)-(3), prepared as disclosed in Gallop et al., U.S. Pat. No.6,972,341 and Gallop et al., U.S. Pat. No. 7,227,028, consist of amixture of two diastereomers ((1S)/(1R)) and are isolated as thick oilsafter concentration from solutions in organic solvents. The oily natureof the materials obtained by the process disclosed in Gallop et al. isundesirable from the perspective of formulating stable, pharmaceuticallyacceptable oral dosage forms. Moreover, it has been found thattransformation of the diastereomeric compounds to certain alkali metalsalt forms (e.g., sodium salts) affords solid materials that aredistinctly hygroscopic. Hygroscopic solids are difficult to handle usingtypical pharmaceutical processing conditions because of low bulkdensities and unsatisfactory flow properties. Moreover, handling ofhygroscopic solids requires special techniques and equipment to obtain,for example, reproducible amounts of active compound or solidformulation stability. Furthermore, drugs that are hygroscopic must bepackaged in special containers that are impervious to water vapor thussubstantially increasing the cost of such products.

SUMMARY

Accordingly, a need exists for forms of(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,and (3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoateand pharmaceutically acceptable salts thereof with physicochemicalproperties that may be used advantageously in pharmaceutical processingand in pharmaceutical compositions.

Forms of Calcium

(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate(5), calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate(6), and calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate (7)are provided that satisfy these and other needs.

In a first aspect, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,which exhibits characteristic scattering angles (2θ) at least at5.4°±0.2° and 14.1°±0.2° in an X-ray powder diffractogram measured usingCu—K_(α) radiation is provided.

In a second aspect, calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,which exhibits characteristic scattering angles (2θ) at least at5.1°±0.2° in an X-ray powder diffractogram is provided measured usingCu—K_(α) radiation is provided.

In a third aspect, calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,which exhibits characteristic scattering angles (2θ) at least at5.3°±0.2°, 9.3°±0.2°, 10.5°±0.2° and 13.9°±0.2° in an X-ray powderdiffractogram measured using Cu—K_(α) radiation is provided.

In a fourth aspect, pharmaceutical compositions are provided comprisingcalcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate;and a pharmaceutically acceptable vehicle.

In a fifth aspect, method of preparing calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate areprovided.

In a sixth aspect, methods of treating a disease in a patient areprovided comprising administering to a patient in need of such treatmenta therapeutically effective amount of a pharmaceutical compositioncomprising calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,wherein the disease is chosen from a movement disorder, agastrointestinal disorder, a psychotic disorder, a mood disorder, ananxiety disorder, a sleep disorder, a pulmonary disorder, aneurodegenerative disorder, an inflammatory disease, neuropathic pain,musculoskeletal pain, chronic pain, migraine, hot flashes, faintnessattacks, urinary incontinence, ethanol withdrawal syndrome, andpremature ejaculation.

In a seventh aspect, kits are provided comprising a pharmaceuticalcomposition comprising calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate andinstructions for administering the pharmaceutical composition to apatient in need thereof for treating a disease chosen from a movementdisorder, a gastrointestinal disorder, a psychotic disorder, a mooddisorder, an anxiety disorder, a sleep disorder, a pulmonary disorder, aneurodegenerative disorder, an inflammatory disease, neuropathic pain,musculoskeletal pain, chronic pain, migraine, hot flashes, faintnessattacks, urinary incontinence, ethanol withdrawal syndrome, andpremature ejaculation.

In an eighth aspect, methods of modulating the α2δ subunit of thevoltage-dependent calcium channel in a patient are provided comprisingadministering a pharmaceutical composition comprising calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate tothe patient.

In a seventh aspect, kits are provided comprising a pharmaceuticalcomposition comprising calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate; anagent chosen from an opioid agonist, a selective serotonin re-uptakeinhibitor, and a selective noradrenaline re-uptake inhibitor; andinstructions for administering the pharmaceutical composition to apatient in need thereof for managing chronic pain.

In an eighth aspect, methods of managing chronic pain in a patient areprovided comprising administering to a patient in need of such treatmenta pharmaceutical composition comprising calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate; anagent chosen from an opioid agonist, a selective serotonin re-uptakeinhibitor, and a selective noradrenaline re-uptake inhibitor; and apharmaceutically acceptable vehicle.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an X-ray powder diffractogram of calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoatecrystallized from acetone/hexane.

FIG. 2 illustrates an X-ray powder diffractogram of calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoatecrystallized from isopropanol/water.

FIG. 3 illustrates an X-ray powder diffractogram of calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoatecrystallized from methanol/diisopropyl ether.

FIG. 4 shows an X-ray powder diffractogram of crystalline calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoatehydrate crystallized from ethanol/water.

DETAILED DESCRIPTION Definitions

“Bioavailability” refers to the amount of a drug that reaches thesystemic circulation of a patient following administration of the drugor prodrug thereof to the patient and may be determined by evaluating,for example, the plasma or blood concentration-versus-time profile for adrug. Parameters useful in characterizing a plasma or bloodconcentration-versus-time curve include the area under the curve (AUC),the time to maximum concentration (T_(max)), and the maximum drugconcentration (C_(max)), where C_(max) is the maximum concentration of adrug in the plasma or blood of a patient following administration of adose of the drug or prodrug thereof to the patient, and T_(max) is thetime to the maximum concentration (C_(max)) of a drug in the plasma orblood of a patient following administration of a dose of the drug orprodrug thereof to the patient.

Calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoaterefers to a salt comprising the anion(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or (3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,respectively, and the calcium (2+) cation in a [2:1] molar ratio.

“Crystalline” means having a regularly repeating arrangement ofmolecules.

“Disease” refers to a disease, disorder, condition, symptom, orindication.

“Patient” includes mammals, such as for example, humans.

“Pharmaceutical composition” refers to a composition comprising at leastone compound provided by the present disclosure and at least onepharmaceutically acceptable vehicle with which the compound isadministered to a patient.

“Pharmaceutically acceptable” refers to approved or approvable by aregulatory agency of a federal or a state government, listed in the U.S.Pharmacopeia, or listed in other generally recognized pharmacopeia foruse in mammals, including humans.

“Pharmaceutically acceptable vehicle” refers to a pharmaceuticallyacceptable diluent, a pharmaceutically acceptable adjuvant, apharmaceutically acceptable excipient, a pharmaceutically acceptablecarrier, or a combination of any of the foregoing with which calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate canbe administered to a patient and which does not destroy thepharmacological activity thereof and which is nontoxic when administeredin doses sufficient to provide a therapeutically effective amount of thecompound.

“Promoiety” refers to a group bonded to a drug, typically to afunctional group of the drug, via bond(s) that are cleavable underspecified conditions of use. The bond(s) between the drug and promoietymay be cleaved by enzymatic or non-enzymatic means. Under the conditionsof use, for example following administration to a patient, the bond(s)between the drug and promoiety may be cleaved to release the parentdrug. The cleavage of the promoiety may proceed spontaneously, such asvia a hydrolysis reaction, or may be catalyzed or induced by anotheragent, such as by an enzyme, by light, by acid, or by a change of orexposure to a physical or environmental parameter, such as a change oftemperature, pH, etc. The agent may be endogenous to the conditions ofuse, such as an enzyme present in the systemic circulation to which theprodrug is administered or the acidic conditions of the stomach or theagent may be supplied exogenously. For example, the promoiety of(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoateis:

the promoiety of(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoateis:

and the promoiety of(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate is:

“Sustained release” refers to release of a therapeutic or preventiveamount of a drug or an active metabolite thereof over a period of timethat is longer than that of an immediate release formulation of thedrug. For oral formulations, the term “sustained release” typicallymeans release of the drug within the gastrointestinal tract lumen over atime period ranging, for example, from about 2 to about 30 hours, and incertain embodiments, over a time period ranging from about 4 to about 24hours. Sustained release formulations achieve therapeutically effectiveconcentrations of the drug in the systemic circulation over a prolongedperiod of time relative to that achieved by oral administration of animmediate release formulation of the drug.

“Treating” or “treatment” of any disease or disorder refers to arrestingor ameliorating a disease, disorder, or at least one of the clinicalsymptoms of a disease or disorder, reducing the risk of acquiring adisease, disorder, or at least one of the clinical symptoms of a diseaseor disorder, reducing the development of a disease, disorder or at leastone of the clinical symptoms of the disease or disorder, or reducing therisk of developing a disease or disorder or at least one of the clinicalsymptoms of a disease or disorder. “Treating” or “treatment” also refersto inhibiting the disease or disorder, either physically, (e.g.,stabilization of a discernible symptom), physiologically, (e.g.,stabilization of a physical parameter), or both, and to inhibiting atleast one physical parameter which may or may not be discernible to thepatient. In certain embodiments, “treating” or “treatment” refers todelaying the onset of the disease or disorder or at least one or moresymptoms thereof in a patient which may be exposed to or predisposed toa disease or disorder even though that patient does not yet experienceor display symptoms of the disease or disorder.

“Therapeutically effective amount” refers to the amount of a compoundthat, when administered to a subject for treating a disease or disorder,or at least one of the clinical symptoms of a disease or disorder, issufficient to affect such treatment of the disease, disorder, orsymptom. A “therapeutically effective amount” can vary depending, forexample, on the compound, the disease, disorder, and/or symptoms of thedisease or disorder, severity of the disease, disorder, and/or symptomsof the disease or disorder, the age, weight, and/or health of thepatient to be treated, and the judgment of the prescribing physician. Anappropriate amount in any given instance can be readily ascertained bythose skilled in the art or capable of determination by routineexperimentation.

Mesophasic Forms of (3S)-Aminomethyl-5-Methyl-Hexanoic Acid Prodrugs

Individual diastereomers of compounds (1), (2), and (3) each formcalcium salts that differ in their propensity to be isolated ascrystalline solids. Thus, for each pair of diastereomeric salts calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoateand calcium(3S)-{[(1S)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate;calcium(3S)-{[(1R)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoateand calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate;and calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate andcalcium(3S)-{[(1S)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate, ithas been found that one isomer, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate(5), calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate(6), and calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate (7)respectively, is more readily isolated in morphologically crystallineform. Characterization of the properties of these materials by X-raypowder diffraction (XRPD) reveals that these salts form mesophasicmaterials as evidenced by diffractograms that are dominated by intense,low angle 2θ reflections. Mesophasic materials typically display longrange molecular order within the crystal lattice but shorter rangedisorder and are sometimes termed liquid crystals.

Mesophasic Calcium

(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate(5), mesophasic calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate(6), and mesophasic calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate (7)and methods of making the mesophasic forms of calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate(5), mesophasic calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate(6), and mesophasic calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate (7)are disclosed in detail herein.

Reference to Calcium

(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoateincludes all possible tautomeric forms of the conventional chemicalstructure for these compounds and all isotopically labeled derivativesof these compounds (e.g., ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, etc.).

Calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate(5) can be synthesized following the methods described in Scheme 1.

O-(1-Isobutanoyloxyethyl) S-methyl thiocarbonate (8), prepared as aracemic mixture according to procedures disclosed in Gallop et al., U.S.Pat. No. 7,227,028, can be treated with an appropriate esterase orlipase (e.g., lipase from Candida antarctica) in aqueous media(optionally buffered at around pH 7) to selectively degrade theS-enantiomer and provide the desired R-enantiomer (9) with highenantioselectivity and good yield. Conversion of (9) to[((1R)-isobutanoyloxyethoxy)carbonyloxy] succinimide (10) and couplingwith pregabalin following the protocols described in Gallop et al., U.S.Pat. No. 7,227,028 provides the free acid form of pregabalin prodrug(1-R). Treatment of (1-R) in an aqueous/organic solvent mixture with 1molar equivalent of a suitable sodium base (e.g., sodium bicarbonate,sodium carbonate, sodium hydroxide, sodium alkoxide) affords the sodiumsalt (11), which may be isolated as a hygroscopic solid after solventremoval in vacuo. Treatment of an aqueous solution of (11) with awater-soluble calcium salt (e.g., calcium acetate, or calcium chloride)provides compound (5) as a white solid that precipitates from solutionand which can be isolated by filtration or centrifugation.Crystallization of compound (5) from an organic solvent mixture affordscalcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoateas a white crystalline solid. Crystallization of (5) from an aqueoussolvent mixture affords calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoatehydrate as a white crystalline solid. In certain embodiments, thesolvent mixture comprises water and a water-miscible alcohol andcompound (5) can be isolated as a white, crystalline hydrate salt. Incertain embodiments, the water-miscible alcohol is chosen from methanol,ethanol, n-propanol, n-butanol, and isopropanol. In certain embodiments,the water-miscible alcohol is chosen from methanol and isopropanol. Incertain embodiments, the aqueous solvent mixture comprises water andethanol and compound (5) is isolated as a white, crystalline hydratesalt. In certain embodiments, the aqueous solvent mixture compriseswater and isopropanol compound and (5) is isolated as a white,crystalline hydrate salt.

Calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate(6) can be synthesized following the methods described in Scheme 2.

O-(1-Isobutanoyloxyisobutoxy) S-methyl thiocarbonate (12), prepared as aracemic mixture according to procedures disclosed in Gallop et al., U.S.Pat. No. 7,227,028, is treated with an appropriate esterase or lipase toselectively degrade the R-enantiomer and provide the desiredS-enantiomer (13) with high enantioselectivity and good yield. In oneembodiment, the esterase is porcine liver esterase (PLE), stabilized bycomplexation with methoxypolyethylene glycol (mPEG) according to themethod described by Heiss and Gais, Tetrahedron Lett., 1995, 36,3833-3836; and Heiss and Gais, Tetrahedron Asymmetry, 1997, 8,3657-3664. Preferably, this enzymatic resolution reaction is conductedin an organic solvent containing a small quantity of water (e.g., 0.5%to 5% v/v). In one embodiment the solvent is methyl tert-butyl ether(MTBE) containing 1% (v/v) water. Conversion of (13) to[(1S)-isobutanoyloxyisobutoxy)carbonyloxy] succinimide (14) and couplingwith pregabalin following the protocols described in Gallop et al., U.S.Pat. No. 7,227,028 provides the free acid form of pregabalin prodrug(2-S). Alternatively, compound (2-S) can be synthesized by reaction ofpregabalin with(1S)-1-[((3R,4R)-2,5-dioxo-3,4-dibenzoyloxypyrrolidinyl)-oxycarbonyloxy]-2-methylpropyl2-methylpropanoate, prepared as described in Gallop et al., U.S. Pat.No. 7,227,028. Treatment of (2-S) in an aqueous/organic solvent mixturewith 1 molar equivalent of a suitable sodium base (e.g., sodiumbicarbonate, sodium carbonate, sodium hydroxide, sodium alkoxide)affords the sodium salt (15), which may be isolated as a hygroscopicsolid after solvent removal in vacuo. Treatment of an aqueous solutionof (15) with a water-soluble calcium salt (e.g., calcium acetate,calcium chloride) provides compound (6) as a white solid thatprecipitates from solution and is isolated by filtration orcentrifugation. Crystallization of (6) from appropriate solvent mixturesaffords calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoateas a white crystalline mesophasic solid.

Calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate (7)can be synthesized following the methods described in Scheme 3.O-(1-Benzoyloxyethyl) S-methyl thiocarbonate (16), prepared as a racemicmixture according to procedures disclosed in Gallop et al., U.S. Pat.No. 7,227,028, is treated with an appropriate esterase or lipase (e.g.,lipase from Candida Rugosa) in aqueous media (optionally buffered ataround pH 7) to selectively degrade the S-enantiomer and provide thedesired R-enantiomer (17) with high enantioselectivity and good yield.

Conversion of (17) to [(1R)-benzoyloxyethoxy)carbonyloxy] succinimide(18) and coupling with pregabalin following the protocols described inGallop et al., U.S. Pat. No. 7,227,028 provides the free acid form ofpregabalin prodrug (3-R). Treatment of (3-R) in an aqueous/organicsolvent mixture with 1 molar equivalent of a suitable sodium base (e.g.,sodium bicarbonate, sodium carbonate, sodium hydroxide, sodium alkoxide)affords the sodium salt (19), which may be isolated as a hygroscopicsolid after solvent removal in vacuo. Treatment of an aqueous solutionof (19) with a water-soluble calcium salt (e.g., calcium acetate,calcium chloride) provides compound (7) as a white solid thatprecipitates from solution and is isolated by filtration orcentrifugation. Crystallization of (7) from appropriate solvent mixturesaffords calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate asa white crystalline mesophasic solid.

In certain embodiments, crystalline calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,crystalline calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or crystalline calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate maybe prepared by first adding calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,crystalline calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or crystalline calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,respectively to a solvent mixture to form a solution or suspension. Asused herein, the terms solution and suspension are used interchangeablyand are meant to include embodiments in which a compound is in a solventor solvent mixture regardless of solubility. A solvent combination canbe such that a compound in solution exhibits temperature-dependentsolubility. In general, solvent combinations in which a compound issoluble within a first temperature range, and poorly soluble within asecond temperature range, can be used in the crystallization methodsdisclosed herein. Mixtures of a “good” solvent and an “anti-solvent” canalso be used with temperature dependent solubilization, i.e., dissolvingat elevated temperature and crystallizing at room temperature. Examplesof suitable “good” solvents, i.e., a solvent in which a pregabalinprodrug provided by the present disclosure is soluble, include methanol,ethanol, isopropanol, acetone, methyl isobutyl ketone, tetrahydrofuran,2-methyl tetrahydrofuran, 1,4-dioxane, 1,2-ethandiol, 1,2-propanediol,2-methoxyethanol, 2-ethoxyethanol, and mixtures thereof. Examples ofsuitable “anti-solvents”, i.e., a solvent in which a pregabalin prodrugprovided by the present disclosure exhibits poorly solubility, includewater, diethyl ether, diisopropyl ether, methyl t-butyl ether, toluene,chlorobenzene, alkanes such as pentane, hexane, heptane, octane, nonane,decane, undecane, dodecane, cis- or trans-decalin, cyclohexane,methylcyclohexane and mixtures thereof.

In certain embodiments, the dissolution process can be carried out atelevated temperature, up to and including the boiling point of thesolvent combination. Accordingly, in certain embodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate maybe dissolved in a solvent mixture with heating and optionally, withshaking and stirring. The heated solution may be maintained at elevatedtemperature to ensure complete dissolution of the compound. The heatedsolution may also be filtered at elevated temperature to remove anyundissolved components.

The heated solution can then be slowly cooled to crystallize calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,which may be separated from residual solvent by filtration and/or dryingunder reduced pressure. In certain embodiments, the solution can becooled to between about 0° C. and about 25° C. Other methods known tothose of skill in the crystallization arts, (e.g., solvent evaporation,drowning, chemical reaction, seeding with a small quantity of thedesired crystal form, etc.) may also be employed to crystallize calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate.

In certain embodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoateundergoes a melt transition between about 102° C. and about 111° C.

In certain embodiments, calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoateundergoes a melt transition between about 90° C. and about 104° C.

In certain embodiments, calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoateundergoes a melt transition between about 162° C. and about 170° C. Inother embodiments, crystalline calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoateundergoes a melt transition between about 167° C. and about 168° C.

In certain embodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoateexhibits characteristic scattering angles (2θ) at least at 5.4°±0.2° and14.1°±0.2° in an X-ray powder diffractogram measured using Cu—K_(α)radiation. In certain embodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoateexhibits characteristic scattering angles (2a) at least at 5.4°±0.1° and14.1°±0.1° in an X-ray powder diffractogram measured using Cu—K_(α)radiation.

In certain embodiments, calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,exhibits characteristic scattering angles (2θ) at least at 5.1°±0.2° inan X-ray powder diffractogram measured using Cu—K_(α) radiation. Incertain embodiments, calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,exhibits characteristic scattering angles (2θ) at least at 5.10°±0.1° inan X-ray powder diffractogram measured using Cu—K_(α) radiation.

In certain embodiments, calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoateexhibits characteristic scattering angles (2θ) at least at 5.3°±0.2°,9.3°±0.2°, 10.5°±0.2° and 13.9°±0.2° in an X-ray powder diffractogrammeasured using Cu—K_(α) radiation. In certain embodiments, calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoateexhibits characteristic scattering angles (2θ) at least at 5.3°±0.1°,9.3°±0.1°, 10.5°±0.1° and 13.9°±0.1° in an X-ray powder diffractogrammeasured using Cu—K_(α) radiation.

Therapeutic Uses

The pharmacological activity of (3S)-aminomethyl-5-hexanoic acid isbelieved to be effected through binding to the α2δ subunit ofvoltage-gated calcium channels and the concomitant reduction in thesynaptic release of neurotransmitters such as noradrenaline, glutamate,and substance P (see, e.g., Taylor et al., Epilepsy Res 2007, 73,137-50). Accordingly, administering calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate canbe expected to be useful in treating diseases and disorders associatedwith α2δ subunit of voltage-gated calcium channels. In clinical trials,(3S)-aminomethyl-5-hexanoic acid has been shown to be effective intreating diseases and disorders including, for example, post-operativepain (Dahl et al., Acta Anaesthesiol Scand 2004, 48, 1130-1136);neuropathic pain (Zareba, Drugs Today 2005, 41(8), 509-16; and Blommeland Blommel, Am J Health Syst Pharm 2007, 64(14), 1475-82);chemotherapy-induced pain (Rao et al., Cancer 2007, 110(9), 2110-8; andSaif and Hashmi, Cancer Chemother Pharmacol 2008, 61, 349-354); generalanxiety disorder (Rickels et al., Arch Gen Psychiatry 2005, 62,1022-1030); anxiety (Pohl et al., J Clin Psychopharmacol 2005, 25,151-8); poster-herpetic neuralgia and painful diabetic peripheralneuropathy (Freynhagen et al., Pain 2005, 115, 254-63); sleep disorders(Sabatowski et al., Pain 2004, 109, 26-35; and Hindmarch et al., Sleep2005, 28(2), 187-93); ethanol withdrawal syndrome (Becker et al.,Alcohol & Alcoholism 2006, 41(4), 399-406); fibromyalgia (Crofford etal., Arthritis and Rheumatism 2005, 52, 1264-73); restless legs syndrome(Sommer et al., Acta Neruol Scand 2007, 115(5), 347-50); pain associatedwith spinal cord injury (Siddall et al., Neurology 2006, 67(10),1792-800); social phobia (Pande et al., J Clin Psychopharmacol 2004,24(2), 141-149); and others. A number of studies have shown thatgabapentin, another GABA analog with affinity for the α2δ subunit, isuseful for preventing migraine (see, e.g., Mathew et al., Headache 2001,41, 119-128; Mathew, Cephalalgia 1996, 16, 367; and Wessely et al.,Cephalalgia 1987, 7(Suppl 6), 477-478).

Calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing may be administeredto a patient, such as a human, suffering from treating a disease chosenfrom a movement disorder, a gastrointestinal disorder, a psychoticdisorder, a mood disorder, an anxiety disorder, a sleep disorder, apulmonary disorder, a neurodegenerative disorder, an inflammatorydisease, neuropathic pain, musculoskeletal pain, chronic pain, migraine,hot flashes, faintness attacks, urinary incontinence, ethanol withdrawalsyndrome, and premature ejaculation. Further, in certain embodiments,calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing can be administeredto a patient, such as a human, as a preventative measure against variousdiseases or disorder. Calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing may be administeredas a preventative measure to a patient having a predisposition for amovement disorder, a gastrointestinal disorder, a psychotic disorder, amood disorder, an anxiety disorder, a sleep disorder, a pulmonarydisorder, a neurodegenerative disorder, an inflammatory disease,neuropathic pain, musculoskeletal pain, chronic pain, migraine, hotflashes, faintness attacks, urinary incontinence, ethanol withdrawalsyndrome, and premature ejaculation. Accordingly, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing may be used for theprevention of one disease or disorder and concurrently treating another(e.g., prevention of psychosis while treating a gastrointestinaldisorder; prevention of neuropathic pain while treating ethanolwithdrawal syndrome).

The efficacy of administering calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing for treating amovement disorder, a gastrointestinal disorder, a psychotic disorder, amood disorder, an anxiety disorder, a sleep disorder, a pulmonarydisorder, a neurodegenerative disorder, an inflammatory disease,neuropathic pain, musculoskeletal pain, chronic pain, migraine, hotflashes, faintness attacks, urinary incontinence, ethanol withdrawalsyndrome, or premature ejaculation may be assessed using animal andhuman models of fibromyalgia and on clinical results using methods knownin the art.

Calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing may be used totreat a movement disorder, a gastrointestinal disorder, a psychoticdisorder, a mood disorder, an anxiety disorder, a sleep disorder, apulmonary disorder, a neurodegenerative disorder, an inflammatorydisease, neuropathic pain, musculoskeletal pain, chronic pain, migraine,hot flashes, faintness attacks, urinary incontinence, ethanol withdrawalsyndrome, or premature ejaculation using known procedures described inthe art.

Calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate maybe more efficacious than the parent drug molecule (i.e. pregabalin) intreating a movement disorder, a gastrointestinal disorder, a psychoticdisorder, a mood disorder, an anxiety disorder, a sleep disorder, apulmonary disorder, a neurodegenerative disorder, an inflammatorydisease, neuropathic pain, musculoskeletal pain, chronic pain, migraine,hot flashes, faintness attacks, urinary incontinence, ethanol withdrawalsyndrome, or premature ejaculation because when administered orally thecompound provides for sustained therapeutically effective bloodconcentrations of (3S)-aminomethyl-5-hexanoic acid. It is believed thatmetabolites of calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoatesuch as the anion or protonated form of(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or (3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoateare absorbed from the gastrointestinal lumen into the blood by adifferent mechanism than that by which pregabalin and other known GABAanalogs are absorbed. For example, pregabalin is believed to be activelytransported across the gut wall by a carrier transporter localized inthe human small intestine. In comparison to pregabalin, the compoundsdisclosed herein, are believed to be absorbed across the gut wall alonga greater portion of the gastrointestinal tract, including the colon.

Because metabolites of calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoatesuch as the anion or protonated form of(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or (3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoatecan be absorbed throughout the gastrointestinal tract, including thecolon, the compound can be advantageously formulated in sustainedrelease oral formulations that provide for sustained release of thecompound over a period of hours into the gastrointestinal tract and inparticular, release within the colon, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate mayalso be more efficacious than pregabalin in treating a movementdisorder, a gastrointestinal disorder, a psychotic disorder, a mooddisorder, an anxiety disorder, a sleep disorder, a pulmonary disorder, aneurodegenerative disorder, an inflammatory disease, neuropathic pain,musculoskeletal pain, chronic pain, migraine, hot flashes, faintnessattacks, urinary incontinence, ethanol withdrawal syndrome, andpremature ejaculation. The ability of calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate tobe used in sustained release oral dosage forms can facilitatetherapeutic regimens having a reduced dosing frequency necessary tomaintain a therapeutically effective pregabalin concentration in theblood.

In certain embodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing can be administeredto a patient for treating a movement disorder such as epilepsy,hypokinesia, spasticity, restless legs syndrome. In certain embodiments,calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing can be administeredto a patient to treat restless legs syndrome, and for example, patientswith severe symptoms such as daytime symptoms.

In certain embodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing can be administeredto a patient for treating a gastrointestinal disorder such as irritablebowel syndrome.

In certain embodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing can be administeredto a patient for treating a psychotic disorder such as schizophrenia.

In certain embodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing can be administeredto a patient for treating a mood disorder such as depressive disorder,dysthymic disorder, bipolar I disorder, bipolar II disorder, cyclothymicdisorder, mood disorder. In certain embodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate orpharmaceutical composition of any of the foregoing can be administeredto a patient for treating bipolar I disorder or bipolar II disorder.

In certain embodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing can be administeredto a patient for treating an anxiety disorder such as generalizedanxiety disorder, anxiety induced by drugs or medical problems, panicattacks, panic disorder, phobic disorders such as agoraphobia socialphobia, and specific phobia, obsessive-compulsive disorder,posttraumatic stress disorder, acute stress disorder.

In certain embodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing can be administeredto a patient for treating a sleep disorder such as primary insomnia,primary hypersomnia, narcolepsy, breathing-related sleep disorder,circadian rhythm sleep disorder, a parasomnia, a sleep disorder due to ageneral medical condition, and substance-induced sleep disorder.

In certain embodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing can be administeredto a patient for treating a pulmonary disorder such as asthma, cough, orchronic obstructive pulmonary disease.

In certain embodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing can be administeredto a patient for treating a neurodegenerative disorder such asAlzheimer's disease, Huntington's disease, Parkinson's disease, oramyotrophic lateral sclerosis.

In certain embodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing can be administeredto a patient for treating an inflammatory disease such as a chronicinflammatory airway disorder including asthma, exercise-inducedbronchospasm (EIB), and chronic obstructive pulmonary disease; a chronicinflammatory bowel disease including ulcerative colitis, and Crohn'sdisease; a chronic inflammatory connective tissue disease includinglupus erythematosus, scleroderma, Sjogren's syndrome, poly- anddermatomyositis, vasculitis, and MCTD; a chronic inflammatory jointdisease including rheumatoid arthritis, juvenile chronic arthritis(Still's disease), rheumatoid spondylitis, lupus erythematosus,ankylosing spondylitis, psoriatic arthritis, and reactive arthritis; achronic inflammatory skin disease including psoriasis, diskoid lupuserythematosus, scleroderma, hives, rosacea, dermatitis, and atopicdermatitis; and other diseases associated with inflammation includingspondyloarthropies, cardiomyopathy, atherosclerosis vasculitis, acuterenal disease, chronic renal disease, glomerulonephritis, inflammatoryeye disorders, tuberculosis, chronic cholecystitis, bronchiectasis,Hashimoto's thyroidiitis, silicosis and other pneumoconioses, andhyper-IgG4 disease.

In certain embodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing can be administeredto a patient for treating pain. Pain includes nociceptive pain caused byinjury to bodily tissues and neuropathic pain caused by abnormalities innerves, spinal cord, and/or brain. Pain includes mechanical allodynia,thermal allodynia, hyperplasia, central pain, peripheral neuropathicpain, diabetic neuropathy, breakthrough pain, cancer pain,deafferentation pain, dysesthesia, fibromyalgia syndrome, hyperpathia,incident pain, movement-related pain, myofacial pain, and paresthesia.

In certain embodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing can be administeredto a patient for treating neuropathic pain. There are several types ofneuropathic pain. A classification that relates to the type of damage orrelated pathophysiology causing a painful neuropathy includesneuropathies associated with mechanical nerve injury such as carpaltunnel syndrome, vertebral disk herniation, entrapment neuropathies,ulnar neuropathy, and neurogenetic thoracic outlet syndrome; metabolicdisease associated neuropathies such as diabetic polyneuropathy;neuropathies associated with neurotropic viral disease such as herpeszoster and human immunodeficiency virus (HIV) disease; neuropathiesassociated with neurotoxicity such as chemotherapy of cancer ortuberculosis, radiation therapy, drug-induced neuropathy, and alcoholicneuropathy; neuropathies associated with inflammatory and/or immunologicmechanisms such as multiple sclerosis, anti-sulfatide antibodyneuropathies, neuropathy associated with monoclonal gammopathy,Sjogren's disease, lupus, vasculitic neuropathy, polyclonal inflammatoryneuropathies, Guillain-Barre syndrome, chronic inflammatorydemyelinating neuropathy, multifocal motor neuropathy, paraneoplasticautonomic neuropathy, ganglinoic acetylcholine receptor antibodyautonomic neuropathy, Lambert-Eaton myasthenic syndrome and myastheniagravis; neuropathies associated with nervous system focal ischemia suchas thalamic syndrome (anesthesia dolorosa); neuropathies associated withmultiple neurotransmitter system dysfunction such as complex regionalpain syndrome (CRPS); neuropathies associated with chronic/neuropathicpain such as osteoarthritis, low back pain, fibromyalgia, cancer bonepain, chronic stump pain, phantom limb pain, and paraneoplasticneuropathies; toxic neuropathies (e.g., exposure to chemicals such asexposure to acrylamide, 3-chlorophene, carbamates, carbon disulfide,ethylene oxide, n-hexane, methyl n-butylketone, methyl bromide,organophosphates, polychlorinated biphenyls, pyriminil,trichlorethylene, or dichloroacetylene), focal traumatic neuropathies,phantom and stump pain, monoradiculopathy, and trigeminal neuralgia; andcentral neuropathies including ischemic cerebrovascular injury (stroke),multiple sclerosis, spinal cord injury, Parkinson's disease, amyotrophiclateral sclerosis, syringomyelia, neoplasms, arachnoiditis, andpost-operative/post-surgical pain; mixed neuropathies such as diabeticneuropathies (including symmetric polyneuropathies such as sensory orsensorimotor polyneuropathy, selective small-fiber polyneuropathy, andautonomic neuropathy; focal and multifocal neuropathies such as cranialneuropathy, limb mononeuropathy, trunk mononeuropathy, mononeuropathymultiplex, and asymmetric lower limb motor neuropathy) andsympathetically maintained pain. Other neuropathies include focalneuropathy; glosopharyngeal neuralgia; ischemic pain; trigeminalneuralgia; atypical facial pain associated with Fabry's disease, Celiacdisease, hereditary sensory neuropathy, or B₁₂-deficiency;mono-neuropathies; polyneuropathies; hereditary peripheral neuropathiessuch as Carcot-Marie-Tooth disease, Refsum's disease, Strumpell-Lorraindisease, and retinitis pigmentosa; acute polyradiculoneuropathy; andchronic polyradiculoneuropathy. Paraneoplastic neuropathies includeparaneoplastic subacute sensory neuropathy, paraneoplastic motor neurondisease, paraneoplastic neuromyotonia, paraneoplastic demyelinatingneuropathies, paraneoplastic vasculitic neuropathy, and paraneoplasticautonomic insufficiency. Calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing can be used totreat any of the foregoing types of neuropathic pain. In certainembodiments, the neuropathic pain is chosen frompost-operative/post-surgical pain, post-herpetic neuralgia, peripheralneuropathy, HIV-related neuropathic pain, cancer-related pain, andchemotherapy-induced pain.

In certain embodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing can be administeredto a patient to treat chemotherapy-induced arthralgias, myalgias, and/orneuropathic pain. In certain embodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing can be administeredto a patient to treat HIV-induced neuropathy. In certain embodiments,calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing can be administeredto a patient to treat post-herpetic neuropathy. In certain embodiments,calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing can be administeredto a patient to treat painful diabetic neuropathy. In certainembodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing can be administeredto a patient to treat fibromyalgia.

In certain embodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing can be administeredto a patient for treating an musculoskeletal pain. Musculoskeletalconditions causing tenderness and muscle spasms include fibromyalgia,tension headaches, myofascial pain syndrome, facet joint pain, internaldisk disruption, somatic dysfunction, spinal fractures, vertebralosteomyelitis, polymyalgia rheumatica, atlantoaxial instability,atlanto-occipital joint pain, osteoporotic vertebral compressionfracture, Scheuermann's disease, spondyloysis, spondylolisthesis,kissing spines, sacroiliac joint pain, sacral stress fracture,coccygodynia, failed back syndrome, and mechanical low back or neckpain. In these conditions, muscle spasm is related to local factorsinvolving the affected muscle groups without the increased tone orreflex characteristic of spasticity. Muscle, tendon, ligament,intervertebral disc, articular cartilage, and bone can be involved inmusculoskeletal pain. Disorders that can produce neck and back paininclude muscle strain, ligament sprain, myofascial pain, fibromyalgia,facet joint pain, internal disc disruption, somatic dysfunction, spinalfracture, verterbral osteomyelitis, and polymyalgia rheumatica,atlantoaxial instability and atlanto-occipital joint pain. Calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,can be used to treat any of the foregoing types of musculoskeletal pain.In certain embodiments, musculoskeletal pain is fibromyalgia.

In certain embodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing can be administeredto a patient for treating migraine, including the prevention of migrainein patients in patients having a predisposition for or history ofmigraine.

In certain embodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing can be administeredto a patient for treating a disease chosen from hot flashes, faintnessattacks, urinary incontinence, ethanol withdrawal syndrome, andpremature ejaculation.

In certain embodiments, methods of treatment comprise administering to apatient calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing in an oral dosageformulation. In certain embodiments, methods of treatment compriseadministering to a patient calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing in a sustainedrelease oral dosage formulation. In certain embodiments, methods oftreatment comprise administering to a patient calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing in an oral dosageformulation in which calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate isreleased throughout the gastrointestinal tract, including the colon, toprovide a sustained concentration of (3S)-aminomethyl-5-hexanoic acid inthe systemic circulation of the patient. In such embodiments, thesustained concentration of (3S)-aminomethyl-5-hexanoic acid can bemaintained for at least 6 hours, at least 12 hours, at least 18 hours,or at least 24 hours following administration of a dose of calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing to the patient.

Modes of Administration

Calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing may beadvantageously used in human medicine. As disclosed herein, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing are useful for thetreatment of a movement disorder, a gastrointestinal disorder, apsychotic disorder, a mood disorder, an anxiety disorder, a sleepdisorder, a pulmonary disorder, a neurodegenerative disorder, aninflammatory disease, neuropathic pain, musculoskeletal pain, chronicpain, migraine, hot flashes, faintness attacks, urinary incontinence,ethanol withdrawal syndrome, or premature ejaculation.

When used to treat the above diseases, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing may be administeredor applied singly, or in combination with other agents. Calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing may also beadministered or applied singly or in combination with otherpharmaceutically active agents, including other GABA analogs.

Methods of treatment include administering to a patient in need of suchtreatment a therapeutically effective amount of calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition thereof. The patient may be an animal, suchas a mammal, for example, a human.

Calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing can be administeredorally. Calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing may be administeredby any other convenient route, for example, by infusion or bolusinjection, or by absorption through epithelial or mucocutaneous linings(e.g., oral mucosa, rectal and intestinal mucosa, etc.). Administrationcan be systemic or local. Various delivery systems are known, (e.g.,encapsulation in liposomes, microparticles, microcapsules, capsules,etc.) that can be used to administer calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing. Methods ofadministration include, but are not limited to, intradermal,intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal,epidural, oral, sublingual, intranasal, intracerebral, intravaginal,transdermal, rectally, by inhalation, or topically, particularly to theears, nose, eyes or skin.

In certain embodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing may be deliveredvia sustained release systems, such as an oral sustained release system.

Calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing provides pregabalinupon in vivo administration to a patient. Calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora metabolite of any of the foregoing including(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoateand/or (3S)-aminomethyl-5-methyl-hexanoic acid;(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoateand/or (3S)-aminomethyl-5-methyl-hexanoic acid; or(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoateand/or (3S)-aminomethyl-5-methyl-hexanoic acid, respectively, may beabsorbed into the systemic circulation from the gastrointestinal tracteither by passive diffusion, active transport or by both passive andactive processes.

The promoiety of(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or (3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoatemay be cleaved either chemically and/or enzymatically. One or moreenzymes present in the stomach, intestinal lumen, intestinal tissue,blood, liver, brain or any other tissue of a mammal may cleave thepromoiety of(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or (3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate.The promoiety of(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or (3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoatemay be cleaved prior to absorption by the gastrointestinal tract (e.g.,within the stomach or intestinal lumen) and/or after absorption by thegastrointestinal tract (e.g., in intestinal tissue, blood, liver orother suitable tissue of a mammal). When the promoiety of(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or (3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoateis cleaved prior to absorption by the gastrointestinal tract, pregabalinmay be absorbed into the systemic circulation conventionally (e.g.,mediated, in part, via the large neutral amino acid transporter locatedin the small intestine). When the promoiety of(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or (3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoateis cleaved after absorption by the gastrointestinal tract, thispregabalin prodrug may be absorbed into the systemic circulation eitherby passive diffusion, active transport, or by both passive and activeprocesses.

When the promoiety of(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or (3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoateis cleaved after absorption by the gastrointestinal tract, thispregabalin prodrug may be absorbed into the systemic circulation fromthe large intestine. When the pregabalin prodrug is absorbed by thelarge intestine, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate, ora pharmaceutical composition of any of the foregoing can beadvantageously administered as a sustained release system. In certainembodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate, ora pharmaceutical composition of any of the foregoing can be delivered byoral sustained release administration. When administered using asustained release formulation, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate, ora pharmaceutical composition of any of the foregoing can be administeredtwice per day or once per day.

In certain embodiments, oral administration of an oral sustained releasedosage form comprising calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate canprovide a therapeutically effective concentration of(3S)-aminomethyl-5-hexanoic acid in the blood plasma of a patient for atime period of at least about 4 hours after administration of the dosageform, in certain embodiments, for a time period of at least about 8hours, and in certain embodiments, for a time period of at least about12 hours, and in certain embodiments, for a time period of at leastabout 24 hours.

Pharmaceutical Compositions

Pharmaceutical compositions provided by the present disclosure containcalcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoatetogether with a suitable amount of a pharmaceutically acceptablevehicle, so as to provide a form for proper oral administration to apatient. In certain embodiments, pharmaceutical compositions provided bythe present disclosure contain a therapeutically effective amount ofcalcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoatetogether with a suitable amount of a pharmaceutically acceptablevehicle, so as to provide a form for proper oral administration to apatient. Suitable pharmaceutical vehicles include excipients such asstarch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk,silica gel, sodium stearate, glycerol monostearate, talc, sodiumchloride, dried skim milk, glycerol, propylene, glycol, water, ethanol,etc. Pharmaceutical compositions provided by the present disclosure mayalso contain minor amounts of wetting or emulsifying agents or pHbuffering agents. In addition, auxiliary, stabilizing, thickening,lubricating and coloring agents may be used.

Pharmaceutical compositions comprising calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate maybe manufactured by means of mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping,lyophilizing, or other process known to those skilled in the art ofpharmaceutical formulation. Pharmaceutical compositions may beformulated using one or more pharmaceutically acceptable vehicles thatfacilitate processing calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoateinto oral dosage formulations, such as a sustained release oral dosageformulation.

Pharmaceutical compositions provided by the present disclosure can takethe form of solutions, aqueous or oily suspensions, emulsion, tablets,pills, pellets, capsules, capsules containing liquids, granules,powders, sustained-release formulations, suppositories, emulsions,syrups, elixirs or any other form suitable for oral administration.Orally administered pharmaceutical compositions may contain one or moreoptional agents, for example, sweetening agents such as fructose,aspartame or saccharin, flavoring agents such as peppermint, oil ofwintergreen or cherry coloring agents and preserving agents, to providea pharmaceutically palatable preparation. Moreover, where in tablet orpill form, a pharmaceutical composition may be coated to delaydisintegration and absorption in the gastrointestinal tract, therebyproviding a sustained action over an extended period of time.Selectively permeable membranes surrounding an osmotically activedriving compound are also suitable for orally administering thecompounds and compositions disclosed herein. In these later platforms,fluid from the environment surrounding the capsule is imbibed by thedriving compound, which swells to displace the agent or agentcomposition through an aperture. These delivery platforms can provide anessentially zero order delivery profile as opposed to the spikedprofiles of immediate release formulations. A time delay material suchas glycerol monostearate or glycerol stearate may also be used. Oralpharmaceutical compositions can include pharmaceutically acceptablevehicles such as mannitol, lactose, starch, magnesium stearate, sodiumsaccharine, cellulose, magnesium carbonate, and the like.

For oral liquid preparations such as, for example, suspensions, elixirsand solutions, suitable vehicles include water, saline, alkyleneglycols(e.g., propylene glycol), polyalkylene glycols (e.g., polyethyleneglycol) oils, alcohols, slightly acidic buffers between pH 4 and pH 6(e.g., acetate, citrate, ascorbate at between about 5 mM to about 50mM), etc. Additionally, flavoring agents, preservatives, coloringagents, bile salts, acylcarnitines and the like may be added.

Calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate maybe formulated in rectal or vaginal compositions such as suppositories orretention enemas, e.g., containing conventional suppository bases suchas cocoa butter or other glycerides.

In certain embodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate canbe formulated as a single active agent. In certain embodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate canbe formulated as a mixture with one or more other pregabalin prodrugs orsalts thereof such as(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,and/or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate.

Calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing may be included ina kit that may be used to administer the compound to a patient fortreating a disease. A kit can include a pharmaceutical compositioncomprising calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoatesuitable for administration to a patient and instructions foradministering the pharmaceutical composition to a patient. A kit caninclude one or more containers for containing one or more pharmaceuticalcompositions and may include divided containers such as a divided bottleor a divided foil packet. A container can be any appropriate shape orform which is made of a pharmaceutically acceptable material. Aparticular container can depend on the dosage form and the number ofdosage forms provided. Instructions provided with a kit can includedirections for administration and may include a memory aid. Instructionssupplied with a kit may be printed and/or supplied, for example, as anelectronic-readable medium, a video cassette, an audiotape, a flashmemory device, or may be published on an internet web site ordistributed to a patient as an electronic mail. A memory aid may be awritten memory aid, which contains information and/or instructions forthe physician, pharmacist, and/or patient to facilitate compliance witha dosing regimen. A memory aid may also be mechanical or electronic.When a therapeutic regimen includes administration of calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate andat least on other therapeutic agent, a kit can include the at least oneother therapeutic agent in the same or separate container as the calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,respectively.

In certain embodiments, a kit comprises a pharmaceutical compositioncomprising calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate andinstructions for administering the pharmaceutical composition to apatient in need thereof for treating a disease chosen from a movementdisorder, a gastrointestinal disorder, a psychotic disorder, a mooddisorder, an anxiety disorder, a sleep disorder, a pulmonary disorder, aneurodegenerative disorder, an inflammatory disease, neuropathic pain,musculoskeletal pain, chronic pain, migraine, hot flashes, faintnessattacks, urinary incontinence, ethanol withdrawal syndrome, andpremature ejaculation.

In certain embodiments, a kit comprises a pharmaceutical composition ofcalcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate andinstructions for administering the pharmaceutical composition to apatient in need thereof for managing chronic pain. In certainembodiments, a kit comprises a pharmaceutical composition comprisingcalcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate andan opioid agonist, and instructions for administering the pharmaceuticalcomposition to a patient in need thereof for managing chronic pain. Incertain embodiments, a kit comprises a pharmaceutical compositioncomprising calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,and an opioid agonist, and instructions for administering thepharmaceutical composition to a patient in need thereof for managing lowback pain, muscle pain, cancer pain, arthritis pain, osteoarthritispain, osteoporosis pain, fibromyalgia, pain associated with inflammatorybowel disease, pain associated with irritable bowel syndrome, or painassociated with rheumatoid arthritis.

Methods provided by the present disclosure, include a method ofincreasing the storage lifetime of(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,comprising forming mesophasic calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate;a method of increasing the storage lifetime of(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,comprising forming calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate;and a method of increasing the storage lifetime of(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,comprising forming mesophasic calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate. Incertain embodiments, a method of increasing the storage lifetime of(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,comprises forming mesophasic calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,which exhibits characteristic scattering angles (2θ) at least at5.1°±0.2° in an X-ray powder diffractogram measured using Cu—K_(α)radiation. In certain embodiments, a method of increasing the storagelifetime of(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,comprises forming calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,which exhibits characteristic scattering angles (2θ) at least at5.4°±0.2° and 14.1°±0.2° in an X-ray powder diffractogram measured usingCu—K_(α) radiation. In certain embodiments, a method of increasing thestorage lifetime of(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,comprises forming mesophasic calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,which exhibits characteristic scattering angles (2θ) at least at5.3°±0.2°, 9.3°±0.2°, 10.5°±0.2° and 13.9°±0.2° in an X-ray powderdiffractogram measured using Cu—K_(α) radiation.

Dose

Calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing can generally beused in an amount effective to achieve the intended purpose such as foruse to treat diseases or disorders such as a movement disorder, agastrointestinal disorder, a psychotic disorder, a mood disorder, ananxiety disorder, a sleep disorder, a pulmonary disorder, aneurodegenerative disorder, an inflammatory disease, neuropathic pain,musculoskeletal pain, chronic pain, migraine, hot flashes, faintnessattacks, urinary incontinence, ethanol withdrawal syndrome, or prematureejaculation. Calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing can be administeredin a therapeutically effective amount.

The amount of calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing that will beeffective in the treatment of a particular disease or disorder willdepend on the nature of the disorder or condition, and can be determinedby standard clinical techniques known in the art as previouslydescribed. In addition, in vitro or in vivo assays may optionally beemployed to help identify optimal dosage ranges. The amount of calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing administered willdepend on, among other factors, the subject being treated, the weight ofthe subject, the severity of the affliction, the manner ofadministration and the judgment of the prescribing physician.

A dose may be delivered in a pharmaceutical composition by a singleadministration, by multiple applications or by controlled release. Incertain embodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing can be delivered byoral sustained release administration. A sustained release formulationcomprising calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing can be administeredtwice per day or once per day. Dosing may be repeated intermittently,may be provided alone or in combination with other drugs, and maycontinue as long as required for effective treatment of the disease ordisorder.

In certain embodiments, a dose or multiple doses of calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing can provide betweenabout 10 mg/day and about 2,000 mg/day of(3S)-aminomethyl-5-methyl-hexanoic acid, in certain embodiments betweenabout 50 mg/day and about 1,000 mg/day of(3S)-aminomethyl-5-methyl-hexanoic acid, and in certain embodiments,between about 100 mg/day and about 600 mg/day of(3S)-aminomethyl-5-methyl-hexanoic acid. Dosage ranges may be readilydetermined by methods known to the skilled artisan.

Calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing can be assayed invitro and in vivo, for the desired therapeutic or prophylactic activity,prior to use in humans. A therapeutically effective dose of calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing can providetherapeutic benefit without causing substantial toxicity and adverseside effects. Toxicity and adverse side effects of calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing may be determinedusing standard pharmaceutical procedures and may be readily ascertainedby the skilled artisan. The dose ratio between toxic and adverse sideeffects and therapeutic effect is the therapeutic index. A dose ofcalcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing can provide acirculating concentration of (3S)-aminomethyl-5-methyl-hexanoic acidthat is within a therapeutically effective concentration with little orno toxicity or adverse side effects.

Combination Therapy

In certain embodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing can be used incombination therapy with at least one other therapeutic agent. Calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing and the at leastone other therapeutic agent can act additively or synergistically. Incertain embodiments, a pharmaceutical composition comprising calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate canbe administered concurrently with the administration of anothertherapeutic agent, which can be part of the same pharmaceuticalcomposition as calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate orthe other therapeutic agent can be in a different pharmaceuticalcomposition. In certain embodiments, a pharmaceutical compositioncomprising calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate canbe administered prior to or subsequent to administration of anothertherapeutic agent.

In certain embodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate maybe administered in combination with a crystalline form of calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoatehydrate, another crystalline form of calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate;pregabalin; gabapentin; or a combination of any of the foregoing.

The additional therapeutic agent may be effective for treating amovement disorder, a gastrointestinal disorder, a psychotic disorder, amood disorder, an anxiety disorder, a sleep disorder, a pulmonarydisorder, a neurodegenerative disorder, an inflammatory disease,neuropathic pain, musculoskeletal pain, chronic pain, migraine, hotflashes, faintness attacks, urinary incontinence, ethanol withdrawalsyndrome, or premature ejaculation; or may be effective for treating adisease other than a movement disorder, a gastrointestinal disorder, apsychotic disorder, a mood disorder, an anxiety disorder, a sleepdisorder, a pulmonary disorder, a neurodegenerative disorder, aninflammatory disease, neuropathic pain, musculoskeletal pain, chronicpain, migraine, hot flashes, faintness attacks, urinary incontinence,ethanol withdrawal syndrome, and premature ejaculation. In certainembodiments in which calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing is administeredtogether with an additional therapeutic agent for treating a movementdisorder, a gastrointestinal disorder, a psychotic disorder, a mooddisorder, an anxiety disorder, a sleep disorder, a pulmonary disorder, aneurodegenerative disorder, an inflammatory disease, neuropathic pain,musculoskeletal pain, chronic pain, migraine, hot flashes, faintnessattacks, urinary incontinence, ethanol withdrawal syndrome, andpremature ejaculation, each of the active agents may be used at lowerdoses than when used singly.

The weight ratio of calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate toa second therapeutic agent may be varied and may depend upon theeffective dose of each agent. A therapeutically effective dose of eachcompound can be used. Thus, for example, when calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate iscombined with another therapeutic agent, the weight ratio of thecompound provided by the present disclosure to the second therapeuticagent can be from about 1000:1 to about 1:1000, from about 200:1 toabout 1:200, from about 20:1 to about 1:20, and in certain embodiments,from about 50:1 to about 1:5.

Combinations of calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate anda second therapeutic agent may also be within the aforementioned range,but in each case, an effective dose of each active compound can be used.In such combinations calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate andsecond therapeutic agent may be administered separately or inconjunction. In addition, the administration of one element may be priorto, concurrent with, or subsequent to the administration of anothertherapeutic agent(s). Accordingly, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate maybe used alone or in combination with other therapeutic agents that areknown to be beneficial in treating a movement disorder, agastrointestinal disorder, a psychotic disorder, a mood disorder, ananxiety disorder, a sleep disorder, a pulmonary disorder, aneurodegenerative disorder, an inflammatory disease, neuropathic pain,musculoskeletal pain, chronic pain, migraine, hot flashes, faintnessattacks, urinary incontinence, ethanol withdrawal syndrome, or prematureejaculation, or other therapeutic agents that affect receptors orenzymes that either increase the efficacy, safety, convenience, orreduce unwanted side effects or toxicity of the compounds provided bythe present disclosure. Calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing and the othertherapeutic agent may be co-administered, either in concomitant therapyor in a fixed combination. The additional therapeutic agent may beadministered by the same or different route than the route used toadminister calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing.

In certain embodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing may be administeredto a patient for the treatment of a movement disorder, agastrointestinal disorder, a psychotic disorder, a mood disorder, ananxiety disorder, a sleep disorder, a pulmonary disorder, aneurodegenerative disorder, an inflammatory disease, neuropathic pain,musculoskeletal pain, chronic pain, migraine, hot flashes, faintnessattacks, urinary incontinence, ethanol withdrawal syndrome, or prematureejaculation in combination with a therapy or therapeutic agent known orbelieved to be effective in the treatment of a movement disorder, agastrointestinal disorder, a psychotic disorder, a mood disorder, ananxiety disorder, a sleep disorder, a pulmonary disorder, aneurodegenerative disorder, an inflammatory disease, neuropathic pain,musculoskeletal pain, chronic pain, migraine, hot flashes, faintnessattacks, urinary incontinence, ethanol withdrawal syndrome, andpremature ejaculation, respectively, or in certain embodiments, adisease, disorder, or condition associated with a movement disorder, agastrointestinal disorder, a psychotic disorder, a mood disorder, ananxiety disorder, a sleep disorder, a pulmonary disorder, aneurodegenerative disorder, an inflammatory disease, neuropathic pain,musculoskeletal pain, chronic pain, migraine, hot flashes, faintnessattacks, urinary incontinence, ethanol withdrawal syndrome, or prematureejaculation, respectively.

In certain embodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing may be administeredto a patient for treating migraine in combination with a therapy oranother therapeutic agent known or believed to be effective in treatingmigraine. Drugs useful for treating migraine can prevent a migraine fromoccurring, abort a migraine that is beginning, or relieve pain duringthe migraine episode.

Prophylactic migraine treatments reduce the frequency of migraines andinclude non-steroidal anti-inflammatory agents (NSAIDs), adrenergicbeta-blockers, calcium channel blockers, tricyclic antidepressants,selective serotonin reuptake inhibitors, anticonvulsants, NMDA receptorantagonists, angiotensin converting enzyme (ACE) inhibitors,angiotensin-receptor blockers (ARBs), leukotriene-antagonists, dopamineagonists, selective 5HT-1D agonists, selective 5HT-1F agonists, AMPA/KAantagonists, CGRP (calcitonin gene related peptide) antagonists, NOS(nitric oxide synthase) inhibitors, blockers of spreading corticaldepression, and other therapy. Examples of NSAIDs useful for preventingmigraine include aspirin, ibuprofen, fenoprofen, flurbiprofen,ketoprofen, mefenamic acid, and naproxen. Examples of adrenergicbeta-blockers useful for preventing migraine include acebutolol,atenolol, imilol, metoprolol, nadolol, pindolol, propranolol, andtimolol. Examples of calcium channel blockers useful for preventingmigraine include amlodipine, diltiazem, dotarizine, felodipine,flunarizine, nicardipine, nifedipine, nimodipine, nisoldipine, andverapamil. Examples of tricyclic antidepressants useful for preventingmigraine include amitriptyline, desipramine, doxepin, imipramine,nortriptyline, and protriptyline. Examples of selective serotoninreuptake inhibitors (SSRIs) useful for preventing migraine includefluoxetine, methysergide, nefazodone, paroxetine, sertraline, andvenlafaxine. Examples of other antidepressants useful for preventingmigraine include bupropion, nefazodone, norepinephrine, and trazodone.

Examples of anticonvulsants (antiepileptics) useful for preventingmigraine include divalproex sodium, felbamate, gabapentin, lamotrigine,levetiracetam, oxcarbazepine, tiagabine, topiramate, valproate, andzonisamide. Examples of NMDA receptor antagonists useful for preventingmigraine include dextromethorphan, magnesium, and ketamine. Examples ofangiotensin converting enzyme (ACE) inhibitors useful for preventingmigraine include lisinopril. Examples of angiotensin-receptor blockers(ARBs) useful for preventing migraine include candesartan. Examples ofleukotriene-antagonists useful for preventing migraine include zileuton,zafirlukast, montelukast, and pranlukast. Examples of dopamine agonistsuseful for preventing migraine include α-dihydroergocryptine. Examplesof other therapy useful for preventing migraine include botulinum toxin,magnesium, hormone therapy, riboflavin, methylergonovine,cyproheptadine, and phenelzine, and complementary therapies such ascounseling/psychotherapy, relaxation training, progressive musclerelaxation, guided imagery, diaphragmatic breathing, biofeedback,acupuncture, and physical and massage therapy.

Acute migraine treatments intended to eliminate or reduce the severityof the headache and any associated symptoms after a migraine has beguninclude serotonin receptor agonists, such as triptans(5-hydroxytryptophan (5-HT) agonists) such as almotriptan, eletriptan,frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan;ergotamine-based compounds such as dihydroergotamine and ergotamine;antiemetics such as metoclopramide and prochlorperazine; and compoundsthat provide analgesic effects.

Other examples of drugs used to treat migraine once started include,acetaminophen-aspirin, caffeine, cyproheptadine, methysergide, valproicacid, NSAIDs such as diclofenac, flurbiprofen, ketaprofen, ketorolac,ibuprofen, indomethacin, meclofenamate, and naproxen sodium, opioidssuch as codeine, meperidine, and oxycodone, and glucocorticoidsincluding dexamethasone, prednisone and methylprednisolone.

Calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing may also beadministered in conjunction with drugs that are useful for treatingsymptoms associated with migraine such as nausea and vomiting, anddepression. Examples of useful therapeutic agents for treating orpreventing vomiting include, but are not limited to, 5-HT₃ receptorantagonists such as ondansetron, dolasetron, granisetron, andtropisetron; dopamine receptor antagonists such as prochlorperazine,thiethylperazine, chlorpromazine, metoclopramide, and domperidone;glucocorticoids such as dexamethasone; and benzodiazepines such aslorazepam and alprazolam. Examples of useful therapeutic agents fortreating or preventing depression include, but are not limited to,tricyclic antidepressants such as amitryptyline, amoxapine, bupropion,clomipramine, desipramine, doxepin, imipramine, maprotiline, nefazadone,nortriptyline, protriptyline, trazodone, trimipramine, and venlafaxine;selective serotonin reuptake inhibitors such as fluoxetine, fluvoxamine,paroxetine, and setraline; monoamine oxidase inhibitors such asisocarboxazid, pargyline, phenizine, and tranylcypromine; andpsychostimulants such as dextroamphetamine and methylphenidate.

In certain embodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing may be administeredto a patient for treating neuropathic pain in combination with a therapyor another therapeutic agent known or believed to be effective intreating neuropathic pain. Examples of drugs useful for treating paininclude opioid analgesics such as morphine, codeine, fentanyl,meperidine, methadone, propoxyphene, levorphanol, hydromorphone,oxycodone, oxymorphone, tramadol and pentazocine; non-opioid analgesicssuch as aspirin, ibuprofen, ketoprofen, naproxen, and acetaminophen;non-steroidal anti-inflammatory drugs such as aspirin, choline magnesiumtrisalicylate, diflunisal, salsalate, celecoxib, rofecoxib, valdecoxib,diclofenac, etodolac, fenoprofen, flubiprofen, ibuprofen, indomethacin,ketoprofen, ketorolac, meclofanamate, mefenamic acid, meloxicam,nabumetone, naproxen, oxaprozin, piroxicam, sulindac, and tometin;antiepileptics such as gabapentin, pregabalin, carbamazepine, phenyloin,lamotrigine, and topiramate; antidepressants such as duloxetine,amitriptyline, venlafaxine, nortryptyline, imipramine, and desipramine;local anesthetics such as lidocaine, and mexiletine; NMDA receptorantagonists such as dextropethorphan, memantine, and ketamine; N-typecalcium-channel blockers such as ziconotide; vanilloid receptor-1modulators such as capsaicin; cannabinoid receptor modulators such assativex; neurokinin receptor antagonists such as lanepitant; otheranalgesics such as neurotropin; and other drugs such as desipramine,clonazepam, divalproex, oxcarbazepine, divalproex, butorphanol,valdecoxib, vicoprofen, pentazocine, propoxyhene, fenoprofen, piroxicam,indometnacin, hydroxyzine, buprenorphine, benzocaine, clonidine,flurbiprofen, meperidine, lacosamide, desvenlafaxine, and bicifadine.

In certain embodiments, a drug useful for treating neuropathic pain ischosen from propoxyphene, meperidine, hydromorphone, hydrocodone,morphine, codeine, 2-piperidinol-1-alkanol, eliprodil, ifenprodil,rofecoxib, celecoxib, salicylic acid, diclofenac, piroxicamindomethacin, ibuprofen, naproxen, gabapentin, carbemazepine,pregabalin, topiramate, valproic acid, sumatriptan, elitriptan,rizatriptan, zolmitriptan, naratriptan, flexeril, carisoprodol,robaxisal, norgesic, dantrium, diazepam, chlordiazepoxide, alprazolam,lorazepam, acetaminophen, nitrous oxide, halothane, lidocaine,etidocaine, ropivacaine, chloroprocaine, sarapin, bupivacaine, capsicin,desipramine, amitriptyline, doxepin, perphenazine, protriptyline,tranylcypromine, baclofen, clonidine, mexelitine, diphenhydramine,hydroxyzine, caffeine, prednisone, methyl-prednisone, decadron,sertraline, paroxetine, fluoxetine, tramadol, levodopa,dextromethorphan, substance P antagonists, and botulinum toxin. Incertain embodiments, a drug useful for treating neuropathic pain can bechosen from a nicotine receptor partial agonist. Non-pharmacologicaltherapies for treating neuropathic pain include transcutaneouselectrical nerve stimulation, percutaneous electrical nerve stimulation,and acupuncture.

In certain embodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing may be administeredto a patient for treating post-herpetic neuralgia in combination with atherapy or another therapeutic agent known or believed to be effectivein treating post-herpetic neuralgia. Examples of drugs useful fortreating post-herpetic neuralgia include antiviral agents such asamantadine, acyclovir, cidofovir, desciclovir, deoxyacyclovir,famciclovir, foscamet, ganciclovir, penciclovir, azidouridine,anasmycin, amantadine, bromovinyldeoxusidine, chlorovinyldeoxusidine,cytarbine, didanosine, deoxynojirimycin, dideoxycitidine,dideoxyinosine, dideoxynucleoside, edoxuidine, enviroxime, fiacitabine,foscamet, fluorothymidine, floxuridine, hypericin, interferon,interleukin, isethionate, nevirapine, pentamidine, ribavirin,rimantadine, stavirdine, sargramostin, suramin, trichosanthin,tribromothymidine, trichlorothymidine, vidarabine, zidoviridine,zalcitabine 3-azido-3-deoxythymidine, 2′,3′-dideoxyadenosine (ddA),2′,3′-dideoxyguanosine (ddG), 2′,3′-dideoxycytidine (ddC),2′,3′-dideoxythymidine (ddT), 2′,3′-dideoxy-dideoxythymidine (d4T),2′-deoxy-3′-thia-cytosine (3TC or lamivudime),2′,3′-dideoxy-2′-fluoroadenosine, 2′,3′-dideoxy-2′-fluoroinosine,2′,3′-dideoxy-2′-fluorothymidine, 2′,3′-dideoxy-2′-fluorocytosine,2′,3′-dideoxy-2′,3′-didehydro-2′-fluorothymidine (Fd4T),2′,3′-dideoxy-2′-beta-fluoroadenosine (F-ddA),2′,3′-dideoxy-2′-beta-fluoro-inosine (F-ddI), and2′,3′-dideoxy-2′-beta-fluorocytosine (F-ddC), trisodiumphosphomonoformate, trifluorothymidine, 3′azido-3′ thymidine (AZT),dideoxyinosine (ddI), and idoxuridine.

In certain embodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate ora pharmaceutical composition of any of the foregoing may be used totreat or manage perioperative and acute post surgical pain.Perioperative pain management generally refers to the three phases ofsurgery: preoperative, intraoperative, and postoperative, and the stepsor measures instituted to prevent and alleviate the acute painassociated with surgery. Post-surgical pain, itself, is a complexresponse to tissue trauma during surgery that stimulateshypersensitivity of the central nervous system. The result is pain inareas not directly affected by the surgical procedure. When a patientundergoes surgery, tissues and nerve endings are traumatized, resultingin surgical incisional pain. This trauma overloads the pain receptorsthat send messages to the spinal cord, which becomes over stimulated.There is an initial afferent barrage of pain signals and a secondaryinflammatory response. This combination contributes significantly topost-surgical pain. The resultant central sensitization is a type ofpost-traumatic stress to the spinal cord, which interprets anystimulation as painful and unpleasant. There is what is believed to beperipheral sensitization and central sensitization (increase inexcitability of spinal neurons). These two process cause what is nowreferred to as a spinal “wind up,” which is responsible for a decreasein pain threshold at the site of injury (surgical site) and insurrounding uninjured tissue. An optimal form of pain treatment is toprovide treatment pre-, intra-, and postoperatively to prevent painhypersensitivity development. It is not unusual for a patient to feelpain in movement or physical touch in locations far from the surgicalsite. Given that pain signals the presence of damage or disease withinthe body, the goal of perioperative pain management is to prevent,reduce, or eliminate pain and discomfort associated with surgery, whileminimizing potential side effects and maximizing patient convenience.Poor perioperative pain management increases the possibility ofpost-surgical complications and interferes with patient recovery andreturn to normal activities of daily living. Acute pain in theperioperative setting can also be defined as pain that is present in asurgical patient because of preexisting disease, the surgical procedure,or a combination of disease-related and procedure-related sources.

It is expected that the optimal exposure to pregabalin for theperioperative management of acute post-surgical pain may be a stabletherapeutic plasma concentration with less peak/trough variability. Bymaintaining sustained pregabalin exposure within a narrow therapeuticrange, particularly during surgery and the first 24 hours post surgery,it is anticipated that calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate mayresult in improved efficacy in reducing pain and opioid use in thetarget population. Calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate canbe formulated as immediate release (IR) and sustained release (SR)formulations. Calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate maybe formulated to have both IR and SR components in a single tablet. TheIR component may be included to generate an immediate release in bloodpregabalin concentrations to provide therapeutic levels of pregabalinduring the surgical procedure that may prevent pain hypersensitivity(Woolf, Anesth Analg 1993, 77, 362-79; and Dahl et al., Acta AnesthesiolScand 2004, 48(8), 1130-39). The SR formulation is expected to generatesustained blood pregabalin concentrations to provide longer lastingrelief from pain. Pregabalin has been shown to be useful in treating ormanaging perioperative and acute post-surgical pain (Hill et al., Eur JPain 2001, 5, 119-124; Tiippana et al., Anesth Analg 2007, 104, 1545-56;Jokela et al., Pain 2008, 134, 106-112; Gilron, Curr Opin Anaesthesiol2007, 20, 456-472; and Freedman and O'Hara, Aesthetic Surgery J 2008,28(4), 421-424). In certain embodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate maybe administered in an amount from about 50 mg/day to about 900 mg/day,and in certain embodiments, from about 150 mg/day to about 600 mg/day,to a patient for the treatment of perioperative pain. In certainembodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate maybe administered in an amount such as to provide from about 25mg-equivalents pregabalin/day to about 450 mg-equivalentspregabalin/day, and in certain embodiments, from about 75 mg-equivalentspregabalin/day to about 300 mg-equivalents pregabalin/day to a patientfor the treatment of perioperative pain. Administration may be prior tosurgery, such as for example, one or two days before surgery, on the dayof surgery, and/or from 1 to 20 days post-surgery.

Calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate maybe administered together with another therapeutic agent useful fortreating perioperative pain, such as for example, an opioid agonist. Incertain embodiments, the other therapeutic agent such as an opioidagonist is administered to a patient for treating perioperative pain asa single pharmaceutical composition, which may be as sustained releaseoral formulation. In certain embodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate isadministered together with an opioid agonist chosen from tramadol,tapentadol, and oxycodone for treating perioperative pain.

Calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate orpharmaceutical composition thereof may be administered singly or incombination with another therapeutic agent used to treat or managechronic pain in a patient. Chronic pain is pain that persists for threemonths or more and includes low back pain, muscle pain, cancer pain,arthritis pain, osteoarthritis pain, osteoporosis pain, fibromyalgia,chronic neuropathic pain, chronic postoperative pain, pain associatedwith inflammatory bowel disease, pain associated with irritable bowelsyndrome, and pain associated with rheumatoid arthritis.

Examples of agents used to treat or manage chronic pain include, forexample, acetaminophen, amitriptyline, amytriptyline, aspirin,butorphanol, celecoxib, choline salicylate, diclofenac, diflunisal,duloxetine, etodolac, fentanyl, gabapentin, hydromorphone, hydroxyzine,ibuprofen, imipramine, indomethacin, ketoprofen, lidocaine, meperidine,methadone, morphine, nalbuphine, naproxen, oxycodone, oxymorphone,pentazocine, pramoxine, pregabalin, propoxyphene, rofecoxib, tapentadol,tolmetin, tramadol, trolamine salicylate, and valdecoxib. In certainembodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate maybe administered together with an opioid agonist to treat chronic pain ina patient. Examples of opioid agonists include a phenanthrene such ascodeine, morphine, thebaine, oripavine; a semisynthetic derivative suchas diacetylmorphine (heroin), dihydrocodeine, hydrocodone,hydromorphone, nicomorphine, oxycodone, and oxymorphone; ananilidopiperidine such as fentanyl, alphamethylfentanyl, alfentanil,sufentanil, remifentanil, carfentanyl, and ohmefentanyl; aphenylpiperidine such as pethidine (meperidine), ketobemidone, MPPP,allylprodine, prodine, and PEPAP; a diphenylpropylamine derivative suchas propoxyphene, dextropropoxyphene, dextromoramide, bezitramide,piritramide, methadone, dipipanone, levomethadyl acetate (LAAM),loperamide, and diphenoxylate; a benzomorphan derivative such asdezocine, pentazocine, phenazocine; an oripavine derivative such asbuprenorphine, dihydroetorphine; and etorphine; a morphinan derivativesuch as butorphanol, nalbuphine, levorphanol, and levomethorphan; andothers such as lefetamine, meptazinol, tilidine, tramadol, andtapentadol. In certain embodiments, an opioid agonist is chosen from theopioid agonist is selected from the group consisting of alfentanil,allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide,brifentanil, buprenorphine, butorphanol, carfentanil, clonitazene,codeine, cyclorphen, cyprenorphine, desomorphine, dextromoramide,dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol,dimepheptanol, dimethylthiambutene, dioxyaphetyl butyrate, dipipanone,eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine,etonitazene, fentanyl, heroin, hydrocodone, hydroxymethylmorphinan,hydromorphone, hydroxypethidine, isomethadone, ketobemidone,levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine,meptazinol, metazocine, methadone, methylmorphine, metopon, mirfentanil,morphine, morphine-6-glucuronide, myrophine, nalbuphine, narceine,nicomorphine, norlevorphanol, normethadone, nociceptin/orphanin FQ(N/OFQ), normoφhine, noφipanone, ohmefentanyl, opium, oxycodone,oxymorphone, papavereturn, pentazocine, phenadoxone, phenomorphan,phenazocine, phenoperidine, pholcodine, piminodine, piritramide,propheptazine, promedol, profadol, properidine, propiram, propoxyphene,remifentanil, sufentanil, tapentadol, tramadol, trefentanil, andtilidine. Opioid agonists include compounds exhibiting an agonisticeffect at an opioid receptor including a μ-, κ-, δ-, and/or nociceptinreceptor. An opioid agonist may also exhibit agonist or antagonistactivity at other receptors.

In certain embodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate maybe administered together with an opioid agonist chosen from tramadol,tapentadol, and oxycodone to treat chronic pain in a patient.

Tramadol (1R,2R or1S,2S)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)-cyclohexanol) is asynthetic, centrally acting analgesic that has been widely used forchronic pain management. Its analgesic effect results form two differentpharmacologic actions. Tramadol displays a weak agonstic effect at theμ- and δ-opioid receptors and a weaker affinity for K-opioid receptors(Grond and Sablotzky, Clin Pharmacokinet 2004, 43(13), 879-923)).Tramadol is formulated as a racemic mixture consisting of twoenantiomers. The main activity of the (−)-enantiomer is the inhibitionof the neuronal re-uptake of noradrenaline, whereas the (+)-enantiomerinteracts with μ-opioid receptors and increases serotonin synapticconcentrations by blocking serotonin re-uptake. Once daily tramadolformulations are known (Coluzzi and Mattia, Therapetuics and ClinicalRisk Management 2007, 3(5), 819-29). Tramadol has been shown to beeffective in treating chronic lower back pain (Ruoff et al., ClinicalTher 2003, 25(4), 1123-1141. Tramadol includes the compound(1R,2R)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)-cyclohexanol,(1S,2S)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)-cyclohexanol, theO-desmethyl derivative of any of the foregoing, pharmaceuticallyacceptable salts of any of the foregoing, pharmaceutically acceptableN-oxides of any of the foregoing and pharmaceutically acceptablesolvates of any of the foregoing. Synergistic effects of tramadol andanticonvulsant drugs such as gabapentin and pregabalin for treating painhave been reported (Codd et al., WO 2001/013904; Codd et al., U.S. Pat.No. 6,562,865; Codd et al., Pain 2008, 134, 254-262; Armenta et al., WO2007/052999; and Keskinbora et al., J Pain Symptom Manage 2007, 34,183-189).

Tapentadol ((−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenolhydrochloride; tapentadol HCl) is an analgesic drug having moderateμ-opioid receptor agonist and norepinephrine reuptake inhibition and isshown to have efficacy in acute and chronic pain models (Tzschentke etal., J Pharm Expt'l Ther 2007, 323(1), 265-276).

Advantages of coadministering oxycodone and pregabalin for treatingneuropathic pain are recognized (Gatti et al., Eur Neurol 2009, 61,129-137; and Hanna et al., Eur J Pain 2008, 12, 804-13).

Calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate andthe an opioid agonist may be formulated in the same pharmaceuticalcomposition or separate pharmaceutical compositions. In certainembodiments, a pharmaceutical composition comprising calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,and the an opioid agonist is a sustained release formulation. In certainembodiments, the sustained release formulation may be adapted to beadministered to a patient once per day or twice per day. In certainembodiments, a dosage form may comprise about 50 mg to about 1200 mg ofthe compound of calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,and about 10 mg to about 400 mg of the opioid agonist. In certainembodiments, the ratio of the amount of calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate tothe amount of opioid agonist in a dosage form is from about 1:4 to about4:1.

In certain embodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate maybe administered together with selective serotonin reuptake inhibitor(SSRI) to treat chronic pain in a patient. In certain embodiments, anSSRI is chosen from cericlamine, citalopram, cyanodothiepinD,L-fenfluramine, dapoxetine, demethylsertraline, desmethylcitalopram,escitalopram, femoxetine, fluoxetine, fluvoxamine, ifoxetine,litoxetine, nefazaodone, norfluoxetine, paroxetine, sertraline,trazodone, and zimelidine. An SSRI functions by inhibiting the reuptakeof serotonin by afferent neurons.

In certain embodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate maybe administered together with selective noradrenaline/norepinephrinereuptake inhibitor (SNRI) to treat chronic pain in a patient. In certainembodiments, an SNRI is chosen from atomoxetine, bicifadine, buproprion,desipramine, fezolamine, hydroxybuproprion, lofepramine, maprotiline,mianserin, sibutramine, mirtazepine, nomifensine, oxaprotiline,reboxetine, and viloxazine.

In certain embodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate maybe administered together with a compound that inhibits the reuptake ofboth serotonin and norepinephrine to treat chronic pain in a patient. Incertain embodiments, a compound that inhibits the reuptake of bothserotonin and norepinephrine is chosen from clomipramine,desmethylclomipramine, duloxetine, imipramine, milnacipran,O-desmethylvenlafaxine, and venlafaxine.

Other agents that may be co-administered with calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate orpharmaceutical composition of any of the foregoing for treating chronicpain include nonsteroidal antiinflammatory drugs (NSAIDs) such asaspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen,flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen,ketorolac, meclofenamic acid, mefenamic acid, nabumetone, naproxen,oxaprozin, phenylbutazone, piroxicam, sulindac, tolmetin, and zomepirac;barbiturate sedatives such as amobarbital, aprobarbital, butabarbital,butabital, mephobarbital, metharbital, methohexital, pentobarbital,phenobartital, secobarbital, talbutal, theamylal, and thiopental;benzodiazepines such as chlordiazepoxide, clorazepate, diazepam,flurazepam, lorazepam, oxazepam, temazepam, and triazolam, H₁antagonists such as diphenhydramine, pyrilamine, promethazine,chlorpheniramine, and chlorcyclizine; other sedatives such asglutethimide, meprobamate, methaqualone, and dichloralphenazone;skeletal muscle relaxants such as baclofen, carisoprodol, chlorzoxazone,cyclobenzaprine, methocarbamol, and orphrenadine; NMDA receptorantagonists such as dextromethorphan ((+)-3-hydroxy-N-methylmorphinan),dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine,pyrroloquinoline quinine, andcis-4-(phosphonomethyl)-2-piperidinecarboxylic acid; α-adrenergic activecompounds such as doxazosin, tamsulosin, clonidine, and4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetra-hydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline;tricyclic antidepressants such as amytriptiline, amoxapine,butryiptyline, clomipramine, desipramine, dosulepin hydrochloride,doxepin, imipramine, iprindole, lofepramine, nortriptyline, opipramol,protriptyline, and trimipramine; anticonvulsants such as carbamazepineand valproate; tachykinin (NK) antagonists such as antagonists,(αR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10-,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]na-phthridine-6-13-dione,5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluorom-ethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3-H-1,2,4-triazol-3-one,lanepitant, dapitant, and3-[[2-methoxy-5-(trifluoromethoxy)phenyl]methylamino]-2-phenyl-piperidine(2S,3S); muscarinic antagonists such as oxybutin, tolterodine,propiverine, tropsium chloride, and darifenacin; COX-2 inhibitors suchas celecoxib, rofecoxib and valdecoxib; non-selective COX inhibitorssuch as nitroflurbiprofen; coal-tar analgesics such as paracetamol;neuroleptics such as droperidol; vanilloid receptor agonists such asresinferatoxin; -adrenergic compounds such as propranolol; localanaesthetics such as mexiletine; corticosteriods such as dexamethasone;serotonin receptor agonists and antagonists; cholinergic (nicotinic)analgesics; and PDEV inhibitors, such as sildenafil, vardenafil, andtaladafil.

Calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate andthe other agent for treating pain such as an SSRI, SNRI, a compound thatinhibits the reuptake of both serotonin and norepinephrine, or otheragent for treating pain may be formulated in the same pharmaceuticalcomposition or separate pharmaceutical compositions. In certainembodiments, a pharmaceutical composition comprising calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate andthe other agent for treating chronic pain is a sustained releaseformulation. In certain embodiments, the sustained release formulationmay be adapted to be administered to a patient once per day or twice perday. In certain embodiments, a dosage form may comprise about 50 mg toabout 1,200 mg of calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,and about 10 mg to about 1,200 mg of the other agent for treating pain.In certain embodiments, the ratio of the amount of calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate tothe amount of opioid agonist in a dosage form is from about 1:200 toabout 200:1; from about 1:50 to about 50:1, from about 1:10 to about10:1, and in certain embodiments from about 1:4 to about 4:1.

In certain embodiments, calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate maybe coadministered with baclofen or a baclofen prodrug such as(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chororphenyl)butanoicacid or other baclofen prodrugs disclosed in Gallop et al., U.S. Pat.No. 7,109,239, which is incorporated by reference in its entirety.

EXAMPLES

The following examples describe in detail the preparation, properties,and uses of calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,and calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate. Itwill be apparent to those skilled in the art that many modifications,both to materials and methods, may be practiced without departing fromthe scope of the disclosure.

Example 1 O-[(1R)-Isobutanoyloxyethyl]S-methyl Thiocarbonate (9)

O-(1-Isobutanoyloxyethyl) S-methyl thiocarbonate (180 g), prepared asdescribed in Gallop et al., U.S. Pat. No. 7,227,028, and lipase fromCandida antarctica, immobilized on acrylic resin, (8.0 g) was stirred inphosphate buffered saline, pH 7.2, (1.6 L) at room temperature. Theprogress of the reaction was monitored by ¹H-NMR using the chiralsolvating agent [(R)-(+)-2,2,2-trifluoro-1-(9-anthryl)ethanol] and wascomplete within 16 h. The reaction mixture was diluted with ether andthe ether layer separated and filtered through a pad of Celite to removethe enzyme. The ether phase was washed repeatedly with water then brine,and dried over anhydrous Na₂SO₄. Removal of the solvent in vacuoafforded a quantitative yield (90 g) of the title compound (9) as asingle enantiomer. The absolute configuration was established by: (i)conversion to compound (10) (see Example 2 below); (ii) reaction of (10)with gabapentin to afford1-{[(α-(R)-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid; and (iii) correlation with the product formed bystereoselective Baeyer-Villiger oxidation of1-{[(α-(R)-isobutanoylethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid as described in Gallop et al., U.S. Pat. No. 6,927,036. ¹H NMR(CDCl₃, 400 MHz): δ 1.16 (3H, d, J=7.6 Hz), 1.18 (3H, d, J=7.0 Hz), 1.50(3H, d, J=5.6 Hz), 2.34 (3H, s), 2.55 (1H, hept, J=7.2 Hz), 6.92 (1H, q,J=5.6 Hz). ¹H NMR in presence of chiral solvating agent,(R)-(−)-2,2,2-trifluoro-1-(9-anthryl)ethanol: 1.18 (6H, m), 1.50 (1.5H,d, J=5.2 Hz), 1.50 (1.5H, d, J=5.6 Hz), 2.33 (1.5H, s), 2.34 (1.5H, s),2.55 (0.5H, sept, J=7.2 Hz), 2.56 (0.5H, sept, J=7.2 Hz), 6.92 (0.5H, q,J=5.6 Hz), 6.92 (0.5H, q, J=5.6 Hz).

Example 2 {[(1R)-Isobutanoyloxyethoxy]carbonyloxy}succinimide (10)

The title compound (10) was prepared from compound (9) by following themethod disclosed in Example 10 of Gallop et al., U.S. Pat. No.7,227,028. ¹H NMR (CDCl₃, 400 MHz): δ 1.17 (d, J=6.8 Hz, 6H), 1.56 (d,J=5.6 Hz, 3H), 2.55 (m, 1H), 2.82 (s, 4H), 6.80 (q, J=5.2 Hz, 1H).

Example 3(3S)-{[(1R)-Isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoicAcid (1-R)

Compound (10) (52.8 g, 0.193 mol) and pregabalin (31.7 g, 0.199 mol)were stirred in a mixture of acetonitrile and water (200 mL, 4:1) atroom temperature for 16 h, and the acetonitrile removed in vacuo. Theresidue was partitioned between MTBE and water, the MTBE layer waswashed with water then brine, and dried over anhydrous Na₂SO₄. Removingthe solvent in vacuo afforded the title compound (1-R) (61.3 g, 100%yield) as a colorless oil. ¹H NMR (CDCl₃, 400 MHz): δ 0.90 (3H, d, J=6.4Hz), 0.92 (3H, d, J=6.4 Hz), 1.17 (8H, m), 1.47 (2.7H, d, J=5.6 Hz),1.50 (0.3H, d, J=5.6 Hz), 1.66 (1H, hept, J=6.8 Hz), 2.19 (m, 1H), 2.27(1H, dd, J=15.2, 7.6 Hz), 2.37 (1H, dd, J=15.2, 5.2 Hz), 2.54 (1H, hept,J=6.8 Hz), 3.08 (1H, m), 3.32 (1H, m), 5.00 (0.9H, br.t, J=6.2 Hz), 5.91(0.1H, br.t, J=6.2 Hz), 6.76 (1H, q, J=5.6 Hz).

Example 4 Calcium(3S)-{[(1R)-Isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate(5)

To a stirred solution of compound (1-R) (16.63 g, 52.5 mmol) inacetonitrile at 0° C. was added an aqueous solution of NaHCO₃ (4.28 g,50.9 mmol) dropwise. The resulting mixture was stirred and sonicated for1 h, then concentrated under reduced pressure to thoroughly removeacetonitrile. To the resulting solution was added dropwise an aqueoussolution of Ca(OAc)₂.H₂O (4.48 g, 25.4 mmol) with stirring at 0° C. Thetitle compound (5) precipitated as a white solid, which was filtered,washed with cold water, then dried in vacuo to afford the title compound(5) as a white solid (10.33 g). The supernatant was lyophilized and theresulting white powder was washed with water to afford a second crop(3.83 g) of the title compound (5). The title compound (5) was furthercrystallized from a variety of solvent systems as described below. ¹HNMR (CD₃OD, 400 MHz): δ 0.90 (6H, t, J=6.6 Hz), 1.14 (3H, d, J=7.2 Hz),1.15 (3H, d, J=6.8 Hz), 1.19 (2H, m), 1.46 (2.7H, d, J=5.6 Hz), 1.48(0.3H, d, J=5.6 Hz), 1.70 (1H, hept, J=6.8 Hz), 2.08 (2H, m), 2.15 (1H,m), 2.52 (1H, hept, J=6.8 Hz), 3.05 (1H, dd, J=13.6, 5.6 Hz), 3.13 (1H,dd, J=13.6, 5.6 Hz), 6.74 (1H, q, J=5.6 Hz).

In an alternate synthesis of compound (5), to a stirred solution of(1-R) (73 g, 0.23 mol) in 450 mL of absolute ethanol at −5° C. wasdropwise added a solution of NaOH (8.83 g, 0.22 mol) in 80 mL of ethanol(addition took ˜2 h to complete). The temperature was maintained below−5° C. during the addition of the basic solution. The reaction mixturewas stirred for another hour at −5° C. and then gradually warmed to roomtemperature. To this stirred solution was added a solution of CaCl₂.2H₂O(16.2 g, 0.11 mol) in 100 mL of ethanol. The resulting reaction mixturewas stirred for 3 h at room temperature and then cooled in an ice bathwithout stirring. Crystalline NaCl was removed by filtration and thesupernatant was concentrated by rotary evaporation to about one third ofthe original volume. De-ionized water was added to the solution to formthe title compound (5) (70.2 g, in two crops, 91% yield), m.p.111.4-116.0° C.

Example 5 O-[(1S)-Isobutanoyloxyisobutyl]S-methyl Thiocarbonate (13)

A mixture of MTBE (990 mL) and water (10 mL) was stirred for 5 h until aclear solution was obtained. To this solution was addedO-(1-isobutanoyloxyisobutyl) S-methyl thiocarbonate (50 g), prepared asdescribed in Gallop et al., U.S. Pat. No. 7,227,028, and a non-covalentcomplex of porcine liver esterase (PLE), with methoxypolyethylene glycol(mPEG) (5 wt %, 75 g) prepared according to the method described byHeiss and Gais, Tetrahedron Lett., 1995, 36, 3833-3836; and Heiss andGais, Tetrahedron Asymmetry, 1997, 8, 3657-3664. The resultingsuspension was stirred at room temperature and the reaction periodicallymonitored by ¹H-NMR using the chiral solvating agent[(R)-(+)-2,2,2-trifluoro-1-(9-anthryl)ethanol]. After approximately 48h, ¹H-NMR indicated that only one enantiomer remained in the reactionmixture at which time the reaction was quenched by filtration through apad of Celite. The supernatant was washed with water, aqueous NaHCO₃then brine, and dried over anhydrous Na₂SO₄. After removing the solventin vacuo, the title compound (13) was isolated as a single S-enantiomer(as determined by HPLC using a chiral column) in 70% yield. The absoluteconfiguration was established by: (i) conversion to compound (14) (seeExample 6 below); (ii) reaction of (14) with R-baclofen to afford4-{[(1S)-isobutanoyloxyisobutoxy]carbonylamino}-(3R)-(4-chlorophenyl)-butanoicacid; and (iii) correlation with the product formed in Example 18 ofGallop et al., U.S. Pat. No. 7,227,028. ¹H NMR (CDCl₃, 400 MHz): δ 0.96(6H, d, J=6.8 Hz), 1.16 (3H, d, J=6.8 Hz), 1.17 (3H, d, J=6.8 Hz),1.98-2.07 (1H, m), 2.32 (3H, s), 2.56 (1H, hept, J=7.2 Hz), 6.67 (1H, d,J=5.6 Hz). ¹H NMR with chiral solvating agent,(R)-(−)-2,2,2-trifluoro-1-(9-anthryl)ethanol: δ 0.98 (3H, d, J=6.8 Hz),0.99 (3H, d, J=6.8 Hz), 1.19 (1.5H, d, J=7.2 Hz), 1.19 (1.5H, d, J=6.8Hz), 1.20 (1.5H, d, J=6.8 Hz), 1.20 (1.5H, d, J=7.2 Hz), 2.01-2.09 (1H,m), 2.34 (1.5H, s), 2.44 (1.5H, s), 2.59 (0.5H, hept, J=7.2 Hz), 2.59(0.5H, hept, J=6.8 Hz), 6.69 (0.5H, d, J=5.6 Hz), 6.70 (0.5H, d, J=5.2Hz).

Example 6 {[(1S)-Isobutanoyloxyisobutoxy]carbonyloxy}succinimide (14)

The title compound (14) was prepared from compound (13) by following themethod disclosed in Example 10 of Gallop et al., U.S. Pat. No.7,227,028.

Example 7(3S)-{[(1S)-Isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoicAcid (2-S)

Compound (14) (10.21 g, 33.9 mmol) and pregabalin (5.5 g, 34.6 mmol)were stirred in a mixture of acetonitrile and water (60 mL, 4:1) for 6 hat room temperature, and then the acetonitrile was removed in vacuo. Theresidue was partitioned between MTBE and water, the MTBE layer washedrepeatedly with water then brine, and dried over anhydrous Na₂SO₄.Removing the solvent in vacuo afforded the title compound (2-S) as acolorless oil (11.65 g, 100% yield). ¹H NMR (CDCl₃, 400 MHz): δ 0.90(6H, t, J=6.8 Hz), 0.97 (6H, J=6.8 Hz), 1.18 (3H, d, J=6.8 Hz), 1.18(3H, d, J=7.2 Hz), 1.19 (2H, m), 1.67 (1H, hept, J=6.8 Hz), 2.03 (1H,m), 2.12 (1H, m), 2.07 (2H, m), 2.56 (1H, hept. J=7.2 Hz), 3.17 (1H, m),3.29 (1H, m), 4.95 (0.83H, br.t, J=6.0 Hz), 5.74 (0.17H, br. t, J=6.0Hz), 6.55 (0.83H, d, J=5.2 Hz), 6.61 (0.17H, br.d, J=4.4 Hz).

Example 8 Calcium(3S)-{[(1S)-Isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate(6)

To a stirred solution of compound (2-S) (8.82 g, 25.5 mmol) inacetonitrile at 0° C. was added an aqueous solution of NaHCO₃ (2.08 g,24.8 mmol) dropwise. The resulting mixture was stirred and sonicated for1 h, then concentrated under reduced pressure to thoroughly removeacetonitrile. To the resulting solution was added dropwise an aqueoussolution of Ca(OAc)₂.H₂O (2.18 g, 12.4 mmol) with stirring at 0° C. Theproduct precipitated as a white solid, which was filtered, washed withcold water, and then dried in vacuo to afford the title compound (6) asa white solid (7.68 g). The supernatant was lyophilized and theresulting white powder was washed with water to afford a second crop ofthe title compound (6). The title compound (6) was further crystallizedfrom a variety of solvent systems as described below. ¹H NMR (CD₃OD, 400MHz): δ 0.84 (6H, t, J=6.8 Hz), 0.93 (3H, d. J=6.8 Hz ), 0.94 (3H, d,J=6.4 Hz), 1.10 (3H, d, J=7.2 Hz), 1.11 (3H, d, J=6.8 Hz), 1.15 (2H, m),1.64 (1H, hept, J=6.8 Hz), 2.03 (4H, m), 2.50 (1H, hept, J=6.8 Hz), 2.97(1H, dd, J=13.2, 5.2 Hz), 3.11 (1H, dd, J=13.2, 5.2 Hz), 6.47 (1H, d,J=5.0 Hz).

Example 9 O-[(1R)-Benzoyloxyethyl]S-methyl Thiocarbonate (17)

O-(1-Benzoyloxyethyl) S-methyl thiocarbonate (50 g), prepared asdescribed in Gallop et al., U.S. Pat. No. 7,227,028, and lipase fromCandida rugosa (2.5 g) were stirred in phosphate buffered saline, pH7.2, (0.5 L) at room temperature. The progress of the reaction wasmonitored by ¹H-NMR using the chiral solvating agent[(R)-(+)-2,2,2-trifluoro-1-(9-anthryl)ethanol] and was complete within16 h. The reaction mixture was diluted with ether and the ether layerseparated and filtered through a pad of Celite to remove the enzyme. Theether phase was washed repeatedly with aqueous sodium bicarbonate thenbrine, and dried over anhydrous Na₂SO₄. Removing the solvent in vacuoafforded 22 g of the title compound (17) as a single enantiomer. ¹H NMR(CDCl₃, 400 MHz): δ 1.65 (3H, d, J=5.6 Hz), 2.35 (3H, s), 7.20 (1H, q,J=5.6 Hz), 7.45 (2H, m), 7.58 (1H, m), 8.06 (2H, m).

Example 10 {[(1R)-Benzoyloxyethoxy]carbonyloxy}succinimide (18)

The title compound (18) was prepared from compound (17) by following themethod disclosed in Example 10 of Gallop et al., U.S. Pat. No.7,227,028. ¹H NMR (CDCl₃, 400 MHz): δ 1.75 (3H, d, J=5.6 Hz), 2.82 (4H,s), 7.07 (1H, q, J=5.4 Hz), 7.45 (2H, m), 7.59 (1H, m), 8.05 (2H, m).

Example 11(3S)-{[(1R)-Benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoic Acid(3-R)

Compound (18) (25.5 g, 83.1 mmol) and pregabalin (13.6 g, 85.4 mmol)were stirred in a mixture of acetonitrile and water (100 mL, 4:1) for 16h at room temperature, and then the acetonitrile was removed in vacuo.The residue was partitioned between MTBE and water, the MTBE layer waswashed repeatedly with water then brine, and dried over anhydrousNa₂SO₄. Removing the solvent in vacuo afforded the title compound (3-R)as a colorless oil (29.09 g, 100% yield). ¹H NMR (CDCl₃, 400 MHz): δ0.88 (6H, t, J=6.8 Hz), 1.17 (2H, m), 1.60 (3H, d, J=5.2 Hz), 1.64 (1H,m), 2.17 (1H, m), 2.27 (1H, dd, J=15.2, 7.6 Hz), 2.35 (1H, dd, J=15.2,5.6 Hz), 3.11 (1H, m), 3.28 (1H, m), 5.06 (0.83H, br.t, J=6.4 Hz), 5.97(0.13H, br.t, J=6.4 Hz), 7.03 (1H, m), 7.41 (2H, m), 7.54 (1H, m), 8.03(2H, m).

Example 12 Calcium(3S)-{[(1R)-Benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate (7)

To a stirred solution of compound (3-R) (13.54 g, 38.5 mmol) inacetonitrile at 0° C. was added an aqueous solution of NaHCO₃ (3.14 g,37.4 mmol) dropwise. The resulting mixture was stirred and sonicated for1 h, then concentrated under reduced pressure to thoroughly removeacetonitrile. To the resulting solution was added dropwise an aqueoussolution of Ca(OAc)₂.H₂O (3.30 g, 18.7 mmol) with stirring at 0° C. Theproduct precipitated as a white solid, which was filtered, washed withcold water, and then dried in vacuo to afford the title compound (7) asa white crystalline solid (12.18 g). The supernatant was lyophilized,and the resulting white powder was washed with water to afford a secondcrop of the title compound (7). The title compound (7) was furthercrystallized from a variety of solvent systems as described herein. ¹HNMR (CD₃OD, 400 MHz): δ 0.83 (3H, d, J=6.8 Hz), 0.84 (3H, d, J=6.4 Hz),1.08 (1H, m) 1.17 (1H, m), 1.54 (3H, d, J=5.6 Hz), 1.63 (1H, m), 2.02(2H, m), 2.17 (1H, m), 2.99 (1H, dd, J=13.6, 5.6 Hz), 3.12 (1H, dd,J=13.6, 5.2 Hz), 6.96 (1H, q, J=5.2 Hz), 7.42 (2H, m), 7.56 (1H, m),7.93 (2H, m).

Example 13 Crystallization of Calcium(3S)-{[(1R)-Isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate(5) from Non-Aqueous Solvents From Acetone-Hexane:

Compound (5) (500 mg) was dissolved in 2 mL of acetone, then hexane (9mL) was added as an anti-solvent. The suspension was warmed to 40° C. toform a clear solution. The solution was cooled to room temperature andleft overnight to permit crystallization. The product was filtered anddried in a vacuum dessicator to afford (5) (338 mg, 67% recovery) as awhite, crystalline solid. m.p. 103.3-117.0° C. An X-ray powderdiffractogram of mesophasic (5) prepared according to this method,obtained as described in Example 17, is shown in FIG. 1.

From THF-Hexane:

Compound (5) (200 mg) was dissolved in 1 mL of THF to form a clearsolution, then hexane (9 mL) as an anti-solvent was added to form asuspension. The suspension was warmed to 45° C. to give a clearsolution. The solution was first cooled first to room temperature andthen to 4° C. to allow crystals to form. The product was filtered anddried in a vacuum dessicator to afford (5) (78 mg, 39% recovery) as awhite, crystalline solid. m.p. 95.5-113.7° C.

Example 14 Crystallization of Calcium(3S)-{[(1S)-Isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate(6) From Isopropanol-Water:

Compound (6) (200 mg) was dissolved in 1.2 mL of isopropanol to form aclear solution. To the solution was added de-ionized water (1.5 mL)dropwise until a suspension started to form. The mixture was warmed to45° C. to give a clear solution. The solution was first cooled to roomtemperature and then to 4° C. to allow crystals to form. The product wasfiltered, dried in a vacuum dessicator at room temperature, and thendried at 45° C. in a vacuum oven overnight to afford (6) (125 mg, 63%recovery) as a white crystalline solid m.p. 90.6-103.9° C. An X-raypowder diffractogram of mesophasic (6) prepared according to thismethod, obtained as described in Example 17, is shown in FIG. 2.

From Acetone-Water:

Compound (6) (200 mg) was dissolved in 1.5 mL of acetone to form a clearsolution. To the solution was added de-ionized water (1.5 mL) dropwiseuntil a suspension started to form. The mixture was warmed to 45° C. togive a clear solution. The solution was first cooled to room temperatureand then to 4° C. to allow crystals to form. The product was filtered,dried in a vacuum dessicator at room temperature, and then dried at 45°C. in a vacuum oven overnight to afford (6) (110 mg, 55% recovery) as awhite crystalline solid m.p. 96.3-121.0° C.

Example 15 Crystallization of Calcium(3S)-{[(1R)-Benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate (7)From Methanol-Diisopropyl Ether:

Compound (7) (0.5 g) was dissolved in methanol (5 mL) at roomtemperature, and diisopropyl ether (˜20 mL) added until the mixturebecame turbid. The mixture was heated to 40° C. to form a clearsolution, and then gradually cooled to room temperature to allowcrystallization. Filtration afforded compound (7) (0.2 g, 40% isolatedyield) as a white crystalline solid m.p. 162.0-166.0° C. An X-ray powderdiffractogram of mesophasic (7) prepared according to this method,obtained as described in Example 17, is shown in FIG. 3.

Example 16 Differential Scanning Calorimetry of Compounds (5), (6), and(7)

Differential scanning calorimetry was performed using a Puris Diamonddifferential scanning calorimeter (DSC) from Perkin Elmer. Followingequilibration at 30° C., sample cells were heated under a nitrogenatmosphere at a rate of 10° C./min to a final temperature of 150° C.Indium metal was used as the calibration standard.

Calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoatecrystallized according to Example 13 exhibited a melt transition fromabout 102° C. to about 111° C.

Calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoatecrystallized according to Example 14 exhibited a melt transition fromabout 90° C. to about 104° C.

Calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoatecrystallized according to Example 15 exhibited a melt transition fromabout 162° C. to about 170° C.; or from about 167° C. to about 168° C.

Example 17 X-Ray Powder Diffraction Analysis of Compounds (5), (6), and(7)

X-ray powder diffraction analyses were performed using either a ShimazduXRD-6000 X-ray powder diffractometer or an Inel XRG-3000 diffractometerusing Cu—Kα radiation (1.54178 Å).

The Shimazdu instrument was equipped with a long fine focus X-ray tube.The tube voltage and amperage were set to 40 kV and 40 mA, respectively.The divergence and scattering slits were set at 10 and the receivingslit was set at 150 μm. Diffracted radiation was detected by a NaIscintillation detector. A θ-2θ continuous scan at 3′/min from 2.5 to 40°2θ was used. A silicon standard was analyzed to confirm the instrumentalignment. Data was collected and analyzed using XRD-6100/7000 v.5.0software. Samples were prepared for analysis by placing a compound on analuminum holder with a silicon insert.

Data was collected on the Inel instrument at a resolution of 0.03° 2θ.The tube voltage and amperage were set to 40 kV and 30 mA, respectively.The monochromator slit was set at 5 mm by 160 μm. The diffractionpatterns were displayed from 2.5 to 40° 2θ. Samples were prepared foranalysis by packing a compound into thin-walled glass capillaries. Eachcapillary was mounted onto a goniometer head that was motorized topermit spinning of the capillary during data acquisition. Samples wereanalyzed for 5 minutes and instrument calibration performed using asilicon reference standard.

Example 18 Intracolonic Bioavailability of Compounds (5), (6), and (7)in Monkeys

Male Cynomologous monkeys weighing about 2.3 kg were used in thestudies. Monkeys were fasted overnight prior to the study until 4 hoursafter dosing. Water was provided ad libitum.

Calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate(5), calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate(6), or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate (7)(obtained as described in Examples 4, 8, and 12, respectively, andbefore crystallization according to Examples 13, 14, and 15,respectively) were prepared as a suspension (21.4 mg/mL) in 0.5% methylcellulose/0.1% Tween-80 in NaH₂PO₄ pH 7.02.

Calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate(5), calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate(6), or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate (7)(1 mL/kg; 10 mg-eq pregabalin/kg) were administered intracolonically to4 monkeys. Blood samples were collected at pre-dose and at 0.17, 0.25,0.5, 1, 2, 4, 6, 8, 12, 18, and 24 hours post-dose. About 0.3 mL ofblood was collected in pre-chilled K₂EDTA tubes. The contents weregently vortexed at low speed to ensure that the sampled blood came intocontact with EDTA while maintaining ice on the samples at all times.About 0.1 mL of the anti-coagulated blood was added to each of 2pre-chilled cryovials that each contained about 0.3 mL of quenchingmedia (i.e., methanol) within 5 minutes of bleed. Each cryovial wasvortexed to ensure thorough mixing of the quenching media. The sampleswere then stored at −70° C.

Blood samples were analyzed by a sensitive and specific LC-MS/MS methodfor simultaneous determination of(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or (3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate;and pregabalin.

As summarized in Table 1, the intracolonic bioavailability (F %, (SD))of pregabalin following intracolonic administration of calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate(5), calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate(6), or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate (7)was determined to be at least 5 times greater than the intracolonicbioavailability of pregabalin following intracolonic administration ofan equivalent dose of pregabalin.

TABLE 1 Intracolonic Bioavailability of Pregabalin Prodrugs IntracolonicBioavailability Compound F_(ic) (%) Pregabalin  4 (2) (5) XP23687 38 (5)(6) XP23608 57 (4) (7) XP23672 45 (6)

Comparative Example 1 Crystallization of Calcium(3S)-{[(1R)-Isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate(5) From Ethanol-Water:

Compound (5) (4 g) was dissolved in 15 mL of absolute ethanol at 45° C.to form a clear solution. To this solution de-ionized water was slowlyadded until turbidity appeared (˜15.5 mL of water). The mixture was thenwarmed to 45° C. to form a clear solution. The solution was cooled toroom temperature to promote crystallization. The solid was filtered,dried in a vacuum dessicator at room temperature, and then dried at 45°C. in a vacuum oven overnight to afford crystalline (5) as a hydrate(3.51 g, 87% recovery) as a white crystalline solid, m.p. 107.1-110.9°C. An X-ray powder diffractogram of crystalline (5) hydrate preparedaccording to this method, obtained as described in Example 17, is shownin FIG. 4. ¹H-NMR (400 MHz, CD₃OD): δ 6.74 (1H, q, J=5.6 Hz), 3.13 (1H,dd, J=13.6, 5.6 Hz), 3.05 (1H, dd, J=13.6, 5.6 Hz), 2.53 (1H, heptett,J=6.4 Hz), 2.08-2.15 (3H, m), 1.68 (1H, heptett, J=6.8 Hz), 1.48 (0.3H,d, J=5.2 Hz), 1.45 (2.7H, d, J=5.2 Hz), 1.10-1.25 (9H, m), 0.88-0.94 (m,7H).

From Ethanol-Water (Alternative Conditions):

Compound (5) (2 g) was dissolved in 12 mL of absolute ethanol at 45° C.to form a clear solution. To this solution de-ionized water was slowlyadded until turbidity appeared (˜24 mL of water). The mixture was thenwarmed to 45° C. to form a clear solution. The solution was slowlycooled to room temperature overnight with the product crystallizing fromsolution. The solid was filtered, dried in a vacuum dessicator at roomtemperature, and then dried at 45° C. in a vacuum oven overnight toafford crystalline (5) as a hydrate (1.4 g, 70% recovery) as a whitesolid, m.p. 110.1-117.0° C.

From Isopropanol-Water:

Compound (5) (6.87 g) was dissolved in 30 mL of isopropanol at 45° C. toform a clear solution, then 70 mL of water was added to afford a turbidmixture. The mixture was warmed to 50° C. to form a clear solution,which was then cooled first to room temperature, then to 4° C. overnightto promote crystallization. The solid was filtered, dried in a vacuumdessicator at room temperature, and then dried at 45° C. in a vacuumoven overnight to afford crystalline (5) as a hydrate (5.06 g, 74%recovery) as a white solid, m.p. 111.7-117.0° C. An X-ray powderdiffractogram of crystalline (5) hydrate prepared according to thismethod, obtained as described in Example 17, exhibited similarcharacteristic diffraction angles as obtained for crystalline (5)hydrate crystallized from ethanol/water.

Example 17 Clinical Trials for Assessing Efficacy in ManagingPerioperative Pain

Based on recent clinical trials performed in patients undergoing varioussurgical procedures such as total abdominal hysterectomy, laparoscopichysterectomy, major laparoscopic surgery, and spinal fusion surgery,pregabalin doses of 150 mg to 300 mg administered 1 to 2 hours prior tosurgery were effective in reducing pain and reducing opioid use (Reubenet al., Anesth Analg 2006, 103(50, 1271-7; Reuben et al., J Bone andJoint Surgery 2007, 89, 1343-58; Buvanendran et al., Anesthesiology2007, 107, 358-359; and Jokela, Pain 2008, 134, 106-112). Based on thesestudies, it is expected C_(max) and AUC_(inf) values for efficaciousdoses of pregabalin for perioperative management of acute post-surgicalpain are predicted to be in the range of 4.73 to 9.46 μg/mL and 33.2 to66.3 μg×hr/mL, respectively.

Efficacy in treating and managing pain can be assessed using one or moreoutcome measures including the Visual Analog Scale (VAS) for pain, thePain Intensity Scale, the Visual Analog Scale for Anxiety, supplementalopioid consumption, patient global assessment of pain control, cognitiveimpairment after surgery, and Range of Motion Composite. The VisualAnalog Scale (VAS) is a straight line with the left end of the linerepresenting no pain and the right end of the line representing theworst pain.

The Pain Intensity Rating scale is one of several differentpain-intensity tools available to qualify pain. Pain Intensity can bemeasured in a numerical format where the individual is asked to identifyhow much pain they are having by choosing a number from 0 (no pain) to10 (the worst pain) on a numerical scale. In the VAS Anxiety Scalepatients rate anxiety on horizontal line from left to right were 0=noanxiety and 100=worst anxiety. Supplemental Opioid Consumption reflectsthe amount of supplemental opioid used to control pain during specifiedtime frame. In the Subject Global Assessment of Pain control patientsrespond at predetermined intervals after surgery how he/she feelsregarding pain control. In the Physician Global Assessment of Paincontrol the physician responds at predetermined intervals after surgeryhow he/she feels regarding pain control in the patient. Cognitiveimpairment can be assessed in a post surgical setting by use of theConfusion Assessment Method Rating Scale (CAM) which was developed as ascreening instrument based on the DSM-IIIR criteria for non psychiatricphysicians in high risk settings. Range of motion assessments may beused to evaluate a patient's ability to flex and extend a particularjoint such as the knee.

A multi-center, randomized, double-blind, placebo-controlled, parallelgroup study of the post-operative analgesic efficacy and safety ofpre-operative dosing of calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate inpatients undergoing bunionectomy is performed.

Male and female study subjects, approximately 50 in each treatment arm,are randomly assigned in a balanced allocation to receive a single oraldose of calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate orplacebo. All patients receive calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate orplacebo approximately 1 hour prior to the surgical incision and haveaccess to patient controlled analgesia (PCA) such as morphine aftersurgery.

Pain intensity reported by patients on the VAS at 2, 4, 6, 12 and 24hours after surgery, the amount of opioid consumed over 24 hoursfollowing surgery, time to first request for rescue PCA pain medicationduring the 24-hour post-surgical period, and the level of sedation atdefined time points after surgery are determined.

Efficacy is assessed by comparing the outcome measures in patientsreceiving calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate andplacebo.

A multi-center, randomized, double-blind, placebo-controlled, parallelgroup dose-ranging study to evaluate the post-operative analgesicefficacy and safety of peri-operative administration of calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate inpatients undergoing primary unilateral total knee arthroplasty isperformed.

On the evening before surgery patients are instructed in the use of the100-mm visual analog scale for pain (VAS Pain) and anxiety (VASAnxiety). Also during this evening visit the instructions on use of apatient controlled anesthesia (PCA) device are provided. Patients arerandomized into one of 5 study arms. Placebo+IV PCA morphine or one of 4doses of calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate(e.g., 150 mg, 300 mg, 600 mg, or 900 mg, or other appropriate dose ordoses)+PCA morphine. On the morning of surgery patients receive calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate orplacebo approximately 1 hour prior to the surgical incision. After adefined period in the recovery room, PCA morphine is made available tothe patient. Patients receive PCA with morphine at doses of 2.5 mg witha lock-out of 10 min for 24 hours postoperatively. Vicodin (hydrocodone7.5 mg/acetaminophen 500 g) is made available 24 hours after surgery toreplace the PCA morphine and patients continue on 300-mg of calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate qAM for the next 5 days as outpatients. Pain control is evaluated duringphysical therapy.

VAS for pain intensity at 2, 4, 6, 12 , 24 and 48 hours after surgery,categorical pain intensity scores in the AM at 48, 72, 96 and 120 hourspost surgery and immediately before scheduled physical rehabilitation,the amounts of IV opioids (morphine equivalents) used following surgeryin 24 hours (time frame of 24 hours), time needed for the first rescuePCA pain medication during the double blind period, the amount of rescue(Vicodin) medication, and the level of sedation at defined time pointsafter surgery are determined. Outcome of the surgical procedure isdetermined using Knee Function Global Endpoint; Pain with Range ofMotion Composite, Knee Function Composite assessments.

Example 18 Animal Model for Assessing Efficacy in ManagingOsteoarthritis Pain

The monosodium iodoacetate rat model for osteoarthritis pain can be usedto assess the efficacy of calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate inmanaging osteoarthritis pain.

Sprague-Dawley male rats weighing 220-230 grams are housed singly inwire cages in sanitary ventilated animal rooms with controlledtemperature, humidity and regular light cycles. Rodent chow and waterare available ad libitum. Animals are acclimated for at least one weekbefore use.

Arthritis is induced by a single intraarticular injection of iodoacetateinto the knee joint of anesthetized rats. A 10 mg/mL solution ofmonosodium iodoacetate is prepared using injectable saline as thevehicle. After appropriate anesthesia each rat is positioned on its backand the left leg is flexed 90 degrees at the knee. The patellar ligamentis palpated below the patella and the injection is made into thisregion. Each rat receives 0.025 mL intra-articular injection into theleft knee. After injection of iodoacetate, rats are treated orally witheither vehicle or test composition, e.g., calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate andan opioid agonist such as tramadol, tapentadol or oxycodone, in vehiclefor 3 weeks or other appropriate time period. Upon termination of thestudy, the left knees of the euthanized animals are disarticulated antthe tibial plateau imaged. The severity of damage in the images isassessed.

The hyperalgesic response can be assessed using the Hargreaves model. Onthe first day of the study, each animal is acclimated to the testequipment and thermal hyperalgesia determined using a Hargreaves PlantarDevice (infrared radiant heat source) to establish baseline pawwithdrawal latency (PWL) values. The baseline PWL values are calculatedas the mean of 2 pre-dose values. Animals are fasted overnight prior todosing. The following day animals are orally dosed with vehicle or testcomposition. Thirty minutes after dosing, each animal is anesthetizedand receives an intraplantar injection of 0.1 mL of a 1.2% solution(w/v) of carrageenan viscarin GP 109 and returned to its cage torecover. Four hours post injection, the left hind limb of each rat isassessed for thermal hyperalgesia. The animals are placed into theHargreaves Plantar Device once again to determine response to the heatstimulus as time to paw withdrawal.

Assessment of punctuate allodynia is evaluated by application of vonFrey hairs in ascending order of force to the plantar surface of thehind paws. Dynamic allodynia is assessed by lightly stroking the plantarsurface of the hind paw with a cotton bud. Paw withdrawal thresholds(PWT) to von Frey hairs and withdrawal latencies to cotton bud stimulusare assessed in the same group of animals on various dayspost-intraarticular injection.

The effect of joint damage on the weight distribution through the right(arthritic) and left (untreated) knee is assessed using an incapacitancetester, which measures weight distribution on the two hind paws.

To determine the inhibitory effects of test composition and opioidagonist on punctuate allodynia and weight bearing deficit, compounds areadministered 14 days (or other appropriate time) post-intraarticularinjection having established stable baseline PWT and weight bearingdeficits prior to drug administration. Animals are administered (onseparate days) with either vehicle or test compound(s) and changes frombaseline assessed for up to 3 hours or other appropriate duration.

Example 19 Animal Model for Assessing Efficacy in Managing Muscle Pain

Adult male Sprague-Dawley rats weighing 250-300 g are used. To inducemuscle pain, recombinant rat TNF diluted in 0.9% NaCl at a concentrationof 1 μg in 50 μL is injected bilaterally either into the gastrocnemiusor into the biceps brachii muscle. The time course of TNF-inducedhyperalgesia is determined in pilot experiments. After injection intothe M. gastrocnemius, pressure hyperalgesia is maximal after about 18hours. After injection of 1 μg TNF into the M. biceps brachii, gripstrength reduction is maximal at about 6 h.

Mechanical withdrawal thresholds to muscle pressure are measured with analgesimeter. Rats are allowed to crawl into a sock which helps the ratto relax. The hind limbs are positioned such that an increasing pressurecould be applied onto the gastrocnemius muscle (maximum 250 g). Thepressure needed to elicit withdrawal is recorded. Both hind limbs aretested ten times (interstimulus interval of >30 s) and means of allwithdrawal thresholds are calculated for each rat.

Grip strength of the fore limbs is tested with a digital grip forcemeters. A rat is positioned to grab the grid with the fore limbs and isgently pulled so that the grip strength can be recorded. Means of tentrials are calculated. Hyperalgesia is assumed if the means of the testsbefore and after TNF injection are significantly different and if thedifference to baseline is at least 1 g for the withdrawal threshold topressure and at least 0.5 g for grip strength.

Rats undergo behavioral testing on three consecutive days before TNFinjections to accustom the animals to the testing procedure. Valuesobtained on the third day are used as a baseline. Separate groups ofrats are then either injected with TNF bilaterally into the M.gastrocnemius and tested for pressure hyperalgesia 18 h later, orinjected with TNF bilaterally into the M. biceps brachii and tested forgrip strength of the fore limbs 6 h later. Calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,or calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate isthen administered and the behavioral tests repeated at appropriate timeintervals following administration.

All rats are monitored for general behavior after drug administration.Sedation ataxia, or other abnormalities of gait, interaction with otheranimals and feeding behavior are observed.

Finally, it should be noted that there are alternative ways ofimplementing the embodiments disclosed herein. Accordingly, the presentembodiments are to be considered as illustrative and not restrictive.Furthermore, the claims are not to be limited to the details givenherein, and are entitled their full scope and equivalents thereof.

1. Calcium(3S)-{[(1R)-isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,which exhibits characteristic scattering angles (2θ) at least at5.4°±0.2° and 14.1°±0.2° in an X-ray powder diffractogram measured usingCu—K_(α) radiation.
 2. The compound of claim 1, which exhibits a meltingpoint range from about 102° C. to about 111° C.
 3. A pharmaceuticalcomposition comprising the compound of claim 1 and a pharmaceuticallyacceptable vehicle.
 4. The pharmaceutical composition of claim 3,comprising a therapeutically effective amount of the compound of claim 1for treating a disease in a patient, wherein the disease is chosen froma movement disorder, a gastrointestinal disorder, a psychotic disorder,a mood disorder, an anxiety disorder, a sleep disorder, a pulmonarydisorder, a neurodegenerative disorder, an inflammatory disease,neuropathic pain, musculoskeletal pain, chronic pain, migraine, hotflashes, faintness attacks, urinary incontinence, ethanol withdrawalsyndrome, and premature ejaculation.
 5. The pharmaceutical compositionof claim 3, wherein the pharmaceutical composition is a sustainedrelease oral dosage formulation.
 6. A method of treating a disease in apatient comprising administering to a patient in need of such treatmenta therapeutically effective amount of the pharmaceutical composition ofclaim 3, wherein the disease is chosen from a movement disorder, agastrointestinal disorder, a psychotic disorder, a mood disorder, ananxiety disorder, a sleep disorder, a pulmonary disorder, aneurodegenerative disorder, an inflammatory disease, neuropathic pain,musculoskeletal pain, chronic pain, migraine, hot flashes, faintnessattacks, urinary incontinence, ethanol withdrawal syndrome, andpremature ejaculation.
 7. A kit comprising the pharmaceuticalcomposition of claim 3 and instructions for administering thepharmaceutical composition to a patient in need thereof for treating adisease chosen from a movement disorder, a gastrointestinal disorder, apsychotic disorder, a mood disorder, an anxiety disorder, a sleepdisorder, a pulmonary disorder, a neurodegenerative disorder, aninflammatory disease, neuropathic pain, musculoskeletal pain, chronicpain, migraine, hot flashes, faintness attacks, urinary incontinence,ethanol withdrawal syndrome, and premature ejaculation.
 8. Thepharmaceutical composition of claim 3, comprising an agent chosen froman opioid agonist, a selective serotonin re-uptake inhibitor, and aselective noradrenaline re-uptake inhibitor.
 9. Calcium(3S)-{[(1S)-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoate,which exhibits characteristic scattering angles (2θ) at least at5.1°±0.2° in an X-ray powder diffractogram measured using Cu—K_(α)radiation.
 10. The compound of claim 9, which exhibits a melting pointrange from about 90° C. to about 104° C.
 11. A pharmaceuticalcomposition comprising the compound of claim 9 and a pharmaceuticallyacceptable vehicle.
 12. The pharmaceutical composition of claim 11,comprising a therapeutically effective amount of the compound of claim 9for treating a disease in a patient, wherein the disease is chosen froma movement disorder, a gastrointestinal disorder, a psychotic disorder,a mood disorder, an anxiety disorder, a sleep disorder, a pulmonarydisorder, a neurodegenerative disorder, an inflammatory disease,neuropathic pain, musculoskeletal pain, chronic pain, migraine, hotflashes, faintness attacks, urinary incontinence, ethanol withdrawalsyndrome, and premature ejaculation.
 13. The pharmaceutical compositionof claim 11, wherein the pharmaceutical composition is a sustainedrelease oral dosage formulation.
 14. A method of treating a disease in apatient comprising administering to a patient in need of such treatmenta therapeutically effective amount of the pharmaceutical composition ofclaim 11, wherein the disease is chosen from a movement disorder, agastrointestinal disorder, a psychotic disorder, a mood disorder, ananxiety disorder, a sleep disorder, a pulmonary disorder, aneurodegenerative disorder, an inflammatory disease, neuropathic pain,musculoskeletal pain, chronic pain, migraine, hot flashes, faintnessattacks, urinary incontinence, ethanol withdrawal syndrome, andpremature ejaculation.
 15. A kit comprising the pharmaceuticalcomposition of claim 11 and instructions for administering thepharmaceutical composition to a patient in need thereof for treating adisease chosen from a movement disorder, a gastrointestinal disorder, apsychotic disorder, a mood disorder, an anxiety disorder, a sleepdisorder, a pulmonary disorder, a neurodegenerative disorder, aninflammatory disease, neuropathic pain, musculoskeletal pain, chronicpain, migraine, hot flashes, faintness attacks, urinary incontinence,ethanol withdrawal syndrome, and premature ejaculation.
 16. Thepharmaceutical composition of claim 11, comprising an agent chosen froman opioid agonist, a selective serotonin re-uptake inhibitor, and aselective noradrenaline re-uptake inhibitort.
 17. Calcium(3S)-{[(1R)-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoate,which exhibits characteristic scattering angles (2θ) at least at5.3°±0.2°, 9.3°±0.2°, 10.50°±0.2° and 13.9°±0.2° in an X-ray powderdiffractogram measured using Cu—K_(α) radiation.
 18. The compound ofclaim 17, which exhibits a melting point range from about 162° C. toabout 170° C.
 19. A pharmaceutical composition comprising the compoundof claim 17 and a pharmaceutically acceptable vehicle.
 20. Thepharmaceutical composition of claim 19, comprising a therapeuticallyeffective amount of the compound of claim 1 for treating a disease in apatient, wherein the disease is chosen from a movement disorder, agastrointestinal disorder, a psychotic disorder, a mood disorder, ananxiety disorder, a sleep disorder, a pulmonary disorder, aneurodegenerative disorder, an inflammatory disease, neuropathic pain,musculoskeletal pain, chronic pain, migraine, hot flashes, faintnessattacks, urinary incontinence, ethanol withdrawal syndrome, andpremature ejaculation.
 21. The pharmaceutical composition of claim 19,wherein the pharmaceutical composition is a sustained release oraldosage formulation.
 22. A method of treating a disease in a patientcomprising administering to a patient in need of such treatment atherapeutically effective amount of the pharmaceutical composition ofclaim 19, wherein the disease is chosen from a movement disorder, agastrointestinal disorder, a psychotic disorder, a mood disorder, ananxiety disorder, a sleep disorder, a pulmonary disorder, aneurodegenerative disorder, an inflammatory disease, neuropathic pain,musculoskeletal pain, chronic pain, migraine, hot flashes, faintnessattacks, urinary incontinence, ethanol withdrawal syndrome, andpremature ejaculation.
 23. A kit comprising the pharmaceuticalcomposition of claim 19 and instructions for administering thepharmaceutical composition to a patient in need thereof for treating adisease chosen from a movement disorder, a gastrointestinal disorder, apsychotic disorder, a mood disorder, an anxiety disorder, a sleepdisorder, a pulmonary disorder, a neurodegenerative disorder, aninflammatory disease, neuropathic pain, musculoskeletal pain, chronicpain, migraine, hot flashes, faintness attacks, urinary incontinence,ethanol withdrawal syndrome, and premature ejaculation.
 24. Thepharmaceutical composition of claim 19, comprising an agent chosen froman opioid agonist, a selective serotonin re-uptake inhibitor, and aselective noradrenaline re-uptake inhibitor.